PROGNOSTIC SIGNIFICANCE AND THERAPEUTIC POTENTIALS OF IMMUNE CHECKPOINTS IN OSTEOSARCOMA - EXCLI Journal
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EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
Review article:
PROGNOSTIC SIGNIFICANCE AND THERAPEUTIC POTENTIALS
OF IMMUNE CHECKPOINTS IN OSTEOSARCOMA
Vafa Meftahpour1,2# , Ali Aghebati-Maleki3# , Ali Fotouhi4 , Elham Safarzadeh5* ,
Leili Aghebati-Maleki1, 6*
1
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
2
Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
3
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
4
Department of Orthopedic Surgery, Faculty of Medicine, Tabriz University of Medical
Sciences, Tabriz, Iran
5
Department of Microbiology, Parasitology, and Immunology, Ardabil University of
Medical Sciences, Ardabil, Iran
6
Department of Immunology, School of Medicine, Tabriz University of Medical Sciences,
Tabriz, Iran
* Corresponding authors: Leili Aghebati-Maleki, Assistant Professor of Immunology,
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Tel: (+98) 413 3364665, Fax: (+98) 41 3364665, E-mail: leili_aghebati_maleki@ya-
hoo.com
Elham Safarzadeh, Assistant Professor of Immunology, Department of Microbiology,
Parasitology, and Immunology, Ardabil University of Medical Sciences, Ardabil, Iran.
E-mail: safarzadeh.elham@gmail.com
#
These authors contributed equally to this work.
https://dx.doi.org/10.17179/excli2021-4094
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/).
ABSTRACT
Although there exist manifold strategies for cancer treatment, researchers are obliged to develop novel treatments
based on the challenges that arise. One of these recent treatment approaches is cancer immunotherapy, which
enjoys various types of strategies itself. However, one of the most significant methods, in this regard, is employing
immune checkpoint proteins (ICPs). Bone sarcomas have several subtypes, with the most common ones being
chordoma, chondrosarcoma, Ewing sarcoma, and osteosarcoma. Although many aggressive treatment approaches,
including radiotherapy, chemotherapy, and surgical resection, have been employed over the last decades, signifi-
cantly improved outcomes have not been observed for Ewing sarcoma or osteosarcoma patients. Additionally,
chordoma and chdrosarcoma resist against both radiation and chemotherapy. Accordingly, elucidating how recent
therapies could affect bone sarcomas is necessary. Checkpoint inhibitors have attracted great attention for the
treatment of several cancer types, including bone sarcoma. Herein, the recent advances of current immune check-
point targets, such as anti-PD-1/PD-L1 and anti-CTLA-4 blockade, for the treatment of bone sarcoma have been
reviewed.
Keywords: Immune checkpoints, osteosarcoma, therapeutic potentials
250EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
INTRODUCTION Consequently, to generally view such treat-
ment strategy, we additionally include studies
As the most frequently occurring malig-
performed on other diseases in this review.
nancy of bone tumor, osteosarcoma (OS) pre-
dominantly takes place in young adults and
adolescents, with an annual incidence rate of BIOLOGY OF THE IMMUNE
8.7 per million children forEXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
Table 1: Clinical trials for osteosarcoma by checkpoint inhibitor
Condition/disease Intervention Eligibility Patients Phase Results Trial number
number
Immune checkpoint inhibitors
Soft Tissue Sarcoma Bone Drug: Pembrolizumab Patients with 12 years 146 II Ongoing and NCT02301039
Sarcoma and older recruiting
Recurrent or refractory solid Biological: Ipilimumab Patients with 12 months 352 I/II Ongoing and NCT02304458
tumors or sarcomas Other: Laboratory Biomarker to 30 years recruiting
Analysis
Biological: Nivolumab Other:
Pharmacological Study
Solid tumors Drug: Atezolizumab Patients with up to 30 100 I/II Ongoing and NCT02541604
years recruiting
Osteosarcoma Drug: Avelumab Patients with 12 years to 40 II Ongoing and NCT03006848
Other: Questionnaires 49 years recruiting
Sarcoma Wilm's Tumor Lym- Drug: Ipilimumab Patients with 3 years to 29 I No major response, but NCT01445379
phoma Neuroblastoma 21 years in the few patients with
regression, it was dura-
ble
Solid tumors Biological: Relatlimab Patients with 12 years 1000 I/II Ongoing and NCT01968109
Biological: Nivolumab and older recruiting
Biological: BMS-986213
Advanced cancers Drug: Imatinib Mesylate Patients with 15 years 96 I Ongoing and NCT01738139
Biological: Ipilimumab and older recruiting
Unspecified Adult Solid Drug: cyclophosphamide Patients with 16 years 12 I Ongoing and NCT02070406
Tumor, Drug: fludarabine phosphate and older recruiting
Protocol Specific Biological: NY-ESO-1 reactive
TCR retroviral vector trans-
duced autologous PBL
Biological: dendritic cell vac-
cine therapy
Biological: aldesleukin
Radiation: fludeoxyglucose F
18
Procedure: positron emission
tomography
Other: laboratory biomarker
analysis
252EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
Table 1 (cont.): Clinical trials for osteosarcoma by checkpoint inhibitor
Condition/disease Intervention Eligibility Patients Phase Results Trial number
number
Refractory or Recurrent Hy- Drug: Nivolumab Patients with 12 months 20 I/II Ongoing and NCT02992964
permutated Malignancies Bi- to 18 years recruiting
allelic Mismatch Repair Defi-
ciency (bMMRD) Positive
Patients
Recurrent solid tumors Drug: Nivolumab, low dose Patients with 1 year to 21 30 I/II Ongoing and NCT02901145
cyclophosphamide years recruiting
Adult Solid Neoplasm Child- Biological: Aldesleukin Patients with 16 years 12 I Ongoing and NCT02775292
hood Solid Neoplasm Drug: Cyclophosphamide and older recruiting
Metastatic Neoplasm Drug: Fludarabine Phosphate
Other: Laboratory Biomarker
Analysis
Biological: Nivolumab
Biological: NY-ESO-1 Reac-
tive TCR Retroviral Vector
Transduced Autologous PBL
Biological: NY-ESO-1(157-
165) Peptide-pulsed Autolo-
gous Dendritic Cell Vaccine
Procedure: Positron Emission
Tomography
Solid Tumor Lymphoma Drug: Durvalumab; MEDI4736 Patients with 1 year to 17 36 I Ongoing and NCT02793466
Central Nervous System years recruiting
Tumors
253EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
Being expressed at the level of immune searchers have proposed that protein phos-
cells throughout their activities, immune phatase activation, for instance PP2A and
checkpoints (ICPs) are molecules of protein SHP2 (also known as PTPN11), could be sig-
that regulate immune cell activity when nificant in counteracting kinase signals in-
bound to their ligand, and prevent them from duced by CD28 and TCR. On the other hand,
progression in the immune responses as well signaling-independent inhibition of T cells is
as damaging normal self-tissues through the conferred by CTLA-4, by sequestering CD86
inhibition of release of immune cell-produced and CD80 from the engagement of CD28, as
toxins (Khosroshahi et al., 2021). It has been well as actively removing CD86 and CD80
reported that the ligands of ICPs are ex- from the surface of the antigen-presenting
pressed at their level to bond with them, re- cells (APCs).
sulting in the evasion of the immune system While the expression of CTLA-4 takes
by the tumor (Khosroshahi et al., 2021). Us- place through activated CD8+ effector T
ing blockers for these molecules improves the cells, its foremost physiological role is sup-
anti-tumor functions of T cells. However, of posed to be within affecting two major CD4+
significance is setting a codified program for T cell subsets: down-modulating the activity
proper application, and determining the opti- of helper T cells and enhancing the immuno-
mal medication dose for treating the disease. suppressive activity of regulatory T (Treg)
cells. The blockade of CTLA-4 leads to an ex-
CTLA-4 tensive augmentation of helper T cell-depend-
As the first ever receptor of the immune ent immune responses. On the other hand,
checkpoint targeted clinically, CTLA-4 en- when engaged on Treg cells, CTLA-4 im-
joys exclusive expression on T cells, where it proves their suppressive functions. Im-
principally modulates the amplitude of the portantly, the forkhead transcription factor
early stages of the activation of T cells. (FOXP3) targets the CTLA-4 gene. It is not
Mainly, the activity of CD28, as a T cell co- known through which mechanisms the immu-
stimulatory receptor, is counteracted by nosuppressive function of Treg cells is en-
CTLA-4. On the condition that cognate anti- hanced by CTLA-4, though Treg cell-specific
gens first engage TCR, CD28 affects T cell blockade or knockout of CTLA-4 considera-
activation. Sharing an almost 30 % identity in bly impedes their ability to control both anti-
amino acids with CD28, CTLA-4 is a member tumor immunity and autoimmunity.
of CD28-B7 immunoglobulin superfamily. The conventional wisdom that underlies
TCR signaling is sharply amplified by CD28 CTLA-4 inhibition is releasing the feedback
signaling upon antigen recognition, which to- inhibition of T cells that have encountered an-
gether activates T cells. Identical ligands are tigens. The first efforts in this regard were
shared by CTLA-4 and CD28; CD86 (also made in 1996 by James Allison and col-
known as B7.2) and CD80 (also known as leagues. It was revealed that when CTLA-4
B7.1). Even though how CTLA-4 functions is antibodies block the activity of CTLA-4 in
not exactly understood, and since CTLA-4 pre-established tumors in several murine
enjoys a greater affinity for both ligands, it is models of tumor, the tumor is rejected. Addi-
suggested that when it is expressed on T cell tionally, immunity against second exposure to
surfaces, T cell activation is reduced through tumor cells was provided to animals by the
outcompeting CD28 for binding to CD86 and antibodies (Aghebati-Maleki et al., 2019; Liu
CD80, along with the active delivery of inhib- et al., 2013, 2014; Wang et al., 2011).
itory signals to the T cell. Such discovery elevated the interest in
In fact, through which signaling pathways this respect, resulting in several clinical trials
the activation of T cells is blocked by CTLA- and the development of Ipilimumab as an en-
4 is still under debate. However, several re- tirely human IgG1 anti-CTLA-4 antibody ap-
254EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
plicable in clinical testing. The success of pre- the genetic polymorphisms of CTLA-4 could
clinical studies and clinical trials eventually have a potential relation to the risk of OS, and
resulted in the FDA approval of Ipilimumab thus could be employed as molecular markers
in 2011. Elevated load of mutations, enhanced in this regard. Together, these results empha-
pretreatment level of tumor infiltrating lym- size the clinical advantages of such therapeu-
phocytes, and amplified tumor antigen spe- tic approach for treating OS.
cific T cells were attributed to improved clin- It has been demonstrated for OS meta-
ical activity. As the first drug successful in static patients that the combined anti-CTLA-
phase III clinical trials for the treatment of late 4 program along with other immune factors
stage metastatic melanoma, Ipilimumab is with significance in this regard could result in
still prominent for improving patient survival. improved anti-tumor activity and prompt re-
Moreover, tremelimumab or IgG2 isotype of covery from the disease. Nevertheless, addi-
CTLA-4 antibody has been employed for the tional experiments are required to obtain the
treatment of metastatic melanoma, beside best outcomes in this respect.
ipilimumab which is IgG1 type of anti-
CTLA-4 antibody. However, tremelimumab PD-1
failed to represent satisfying efficacy in phase PD-1, as another receptor of the immune
III clinical trials (Shang et al., 2013). There checkpoints, has emerged as a recent potential
are still ongoing investigations with regards to target, which emphasizes the variety of im-
tremelimumab, using it as either monotherapy munological manipulations that are molecu-
for metastatic mesothelioma or combined larly defined and enjoy the ability to induce
with other immunotherapeutics for the treat- antitumor immune responses through the im-
ment of cancers such as liver, gastric, pancre- mune system of the patient.
atic, and bladder cancer, as well as squamous The main role attributed to PD-1, as op-
cell carcinoma of the head and neck and non- posed to CTLA-4, is the limitation of T cell
small cell lung cancer. In a recent phase IIb activity in peripheral tissues when there is an
trial, tremelimumab monotherapy did not inflammatory response against infections, as
show survival benefits for metastatic melano- well as limiting autoimmunity. This is trans-
mas. So far, there has been no recognized pre- lated into a key mechanism of immune re-
treatment biomarker applicable as part of sistance inside the microenvironment of the
standard-of-care therapeutic decision-mak- tumor. When T cells are activated, the expres-
ing. However, identifying particular post- sion of PD-1 is induced. Through engagement
treatment immune responses, which are seem- with a ligand, PD-1 is capable of inhibiting
ingly linked to clinical outcomes, has sparked kinases involved in the activation of T cells
insights. The fact that CTLA-4 is considera- by the SHP250 phosphatase, even though
bly linked to the risk of osteosarcoma and there could be other induced signaling path-
could possess important parts in the carcino- ways. Moreover, since the engagement of PD-
genesis of osteosarcoma has been demon- 1 is capable of inhibiting the stop signal of
strated by many meta-analyses (Liu et al., TCR, such pathway could adjust the duration
2013, 2014). In comparison to healthy con- of the contact between T cell–target cell or T
trols (OR 2.27, p=0.010, and OR 1.41, cell–APC. The expression of PD-1 takes
p=0.015), it was shown by Wang et al. that the place highly on Treg cells, which is akin to
frequency of the +49A allele and the CTLA- CTLA-4, enhancing their proliferation when
4 +49AA genotype were meaningfully en- a ligand is present. Blocking PD-1 pathway
hanced in osteosarcoma patients. This sug- might further improve antitumor immune re-
gests that the +49G/A polymorphism of sponses through reducing the suppressive ac-
CTLA-4 gene is linked to enhanced risk of os- tivity and/or the number of intratumoral Treg
teosarcoma (Wang et al., 2011). Additionally, cells, since several tumors have a high Treg
in Chinese Han population, it was shown that
255EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
cell infiltration which presumably suppresses cer is seemingly immune inhibition in the tu-
effector immune responses. mor microenvironment, and since PD-1 is ca-
PD-1 ligand 1 or PD-L1 (also recognized pable of inhibiting the function of lympho-
as B7-H1 and CD274) and PD-L2 (also rec- cytes only when engaged with PD-L1 and
ognized as B7-DC and CD273) are the two PD-L2, it is important to understand the pat-
ligands of PD-1. Sharing a 37 % homology in tern of expression of PD-1 ligands in order to
sequence, these members of the B7 family determine whether they would be suitable in
have arisen by gene duplication, positioning therapy if blocked. There exist two known
them with a 100 kb distance in the genome. PD-L1 expression types; an adaptive mecha-
The recent discovery of the molecular inter- nism triggered through stimulating inflamma-
action between CD80 and PD-L1 led to the tory cytokines, and an innate mechanism trig-
understanding that T-cell- or APC- expressed gered through genetic mutation, with the for-
CD80 might be capable of behaving as a re- mer being mainly caused by IFNγ (Hameed
ceptor instead of a ligand through inhibitory and Dorfman, 2011). High levels of expres-
signal delivery when engaged by PD-L1. sion were initially attributed to most samples
However, the relevance of such interaction in of lung cancer, ovarian cancer, and mela-
the immune resistance of the tumor is yet to noma. Later, the upregulated expression of
be defined. Lastly, the genetic evidence of PD-L1 was also reported for several human
PD-1-deficient T cells puts forward the idea cancers. For one, 50 % of osteosarcomas
that both PD-L2 and PD-L1 might be capable show intermediate, and 23.7 % of them show
of binding to a T cell-expressed co-stimula- high expression levels in this regard (Shen et
tory receptor. Such complicated binding inter- al., 2014b). While the expression of PD-1 is
actions are similar to CD80 and CD86 ligand demonstrated to have a correlation with the
pair, which could bind to CD28 as a co-stim- progression of the osteosarcomas, higher PD-
ulatory receptor expressed on resting T cells L1 expression levels in tumor cells are re-
as well as CTLA-4 as an inhibitory receptor ported to have a positive correlation with
expressed on activated T cells. Nonetheless, TILs in osteosarcoma. Osteosarcoma had 14–
PD-1 mostly controls the activity of effector 75 % higher expression of PD-L1 in tumor
T cells in tumors and tissues, while CTLA-4 tissues, with significant correlation to metas-
principally controls the activation of T cells. tasis and mortality risk, as reported by a re-
To select recombinant ligands and antibodies cent systematic meta-analysis including 868
for clinical use, it is important to understand total patients from 14 studies (Zhu et al.,
the part these various interactions possess in 2017; Shen et al., 2014a).
different cancer settings. As a PD-1 blocking antibody, Nivolumab
The expression of PD-1 takes place more is considered a targeted therapy. Following
broadly as compared to CTLA-4, and its in- nivolumab treatment, partial responses were
duction occurs on other non-T lymphocyte observed in patients with metastatic sarcoma
subsets that are activated, such as natural who had osteosarcoma, epithelioid sarcoma,
killer (NK) cells and B cells, limiting their and dedifferentiated chondrosarcoma
lytic activity. Consequently, while blocking (Veenstra et al., 2018). Interestingly, the reg-
PD-1 is often considered to enhance the activ- ulation of the cell growth of osteosarcoma and
ity of effector T cells in tissues and the tumor resistance against paclitaxel and doxorubicin
microenvironment, it is possible to assume have been attributed to PD-L1 (Liao et al.,
that it improves the activity of NK cells in tis- 2017).
sues and tumors, in addition to enhancing the Recently, promising progress has been
production of antibodies either by directly af- made through tumor immunotherapy target-
fecting PD-1+ B cells or in indirect manners. ing PD-1: PD-L1/PD-L2. However, combin-
Since the primary role of PD-1 ligands in can- ing the application of multiple biomarkers is
256EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
yet to be fully explored. Combining ipili- assays based on RNA in tumor samples and
mumab with nivolumab was shown to bring human osteosarcoma cell lines. Thus, inhibit-
about more survival benefits compared to ing PD-1/PD-L1 could be an interesting ap-
nivolumab monotherapy. proach capable of restoring the function of the
It has been shown in preclinical studies on immune system against osteosarcoma cells (
mouse models that the upregulation of im- Koirala et al., 2016; Shen et al., 2014b; Wang
mune checkpoints, including TIM-3, takes et al., 2016b). It was shown in 2018 that the
place as a result of anti-PD-1 antibody treat- rate of the response of anti-PD-1was greater
ment, which might lead to resistance against compared to that of anti-PD-L1 antibody
anti-PD-1 antibody therapy. The detectable (Shabani et al., 2019). Since CTLA-4 is ex-
soluble PD-L1 (sPD-L1) in the blood is a de- pressed by Tregs, obtaining the anti-tumor
rivative of the alternative variants of the tran- function of anti-CTLA-4 antibody could be
scripts of PD-L1, which might have a relation performed through inhibiting CTLA-4 on
to ICBs-mediated anti-tumor response cyto- Tregs in order to reverse the suppression of
kines, including TNF-α, IFN-γ, or IFN-α. As the activation of T cells (Pardoll, 2012;
compared to patients with high plasma levels Topalian et al., 2012). PD-1 expression on-
of sPD-L1, patients with low plasma levels of Tregl surface has been noted by some studies
sPD-L1 achieved partial or complete response (Liu et al., 2013, 2014; Wang et al., 2011; Wei
in a larger proportion. Additionally, the devel- et al., 2018), and the significance of PD-1 on
opment of the progressive disease in those Tregs has been shown (Liu et al., 2014; Shen
with low plasma levels of sPD-L1 was ob- et al., 2014b). Despite the existence of com-
served in a lower proportion. The association prehensive studies on the relationship be-
of higher levels of sPD-L1 to enhanced tumor tween anti-PD-1 antibody and Treg (Zhu et
grade, larger tumors, and elevated death risk al., 2017), how anti-PD-1 antibody affects
has been reported in clear cell renal cell car- Tregs is yet to be defined. With respect to the
cinoma (ccRCC) patients. It is assumed that use of anti-PD-1 antibody for the treatment of
the immune system of the host is damaged by osteosarcoma, there only exist three interim
sPD-L1, thus cancer progression is promoted, reports on clinical trials (Liao et al., 2017;
reducing the clinical outcomes. Taken to- Shen et al., 2014a; Veenstra et al., 2018) and
gether, the plasma level of sPD-L1 might be a one basic research report (Zheng et al., 2015).
valuable biomarker in the prediction of ICBs Additionally, the mechanism of the expres-
treatment response. There exist three distinct sion of PD-L1 is unknown, even though it is
phase II clinical trials with regards to check- reportedly expressed in osteosarcoma (Wang
point inhibitors on osteosarcoma patients at et al., 2016b). Its antitumor effects have also
present; one using anti-PD-1 antibody Pem- been established in vivo, through the altera-
brolizumab (NCT02301039), and the other tions of the volume of the tumor and overall
two assessing anti-PD-1 antibody Nivolumab survival time of following the administration
without or with anti-CTLA-4 antibody Ipili- of anti-PD-1 antibody in a subcutaneously im-
mumab (NCT02304458 and NCT02500797). planted mouse model of osteosarcoma. Thus,
Therefore, based on the results of these clini- more studies are required to demonstrate the
cal trials, the efficiency of checkpoint inhibi- effect of anti-PD-1 antibodies in osteosar-
tors could be elucidated in osteosarcoma pa- coma patients.
tients. It has been found that PD-1 percentage
is considerably enhanced on both peripheral TIM-3
blood CD8+ and CD4+ T lymphocytes in os- As one of the members of the TIM gene
teosarcoma patients. Also, the progression of family, T-cell immunoglobulin and mucin do-
osteosarcoma has been attributed to PD-1 main-containing-3 (TIM-3) is found in hu-
(Zheng et al., 2015). Moreover, high expres- mans, along with TIM-1 and TIM-4, while
sion level of PD-L1 has been determined by TIM-1 through TIM-8 are found in mice
257EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
(Abdel-Rahman 2016). The TIM family IL-2, tumor necrosis factor-alpha (TNF-α),
members are located on chromosome 5q33.2 and IFN-γ could be inhibited by TIM-3+ PD-
in humans. Among them, the expression of 1+ CD8+ TILs. Using the blockade of PD-1
TIM-3 takes place on CD8+ T cells (myeloid in combination with TIM-3 is more effica-
lineage cells), Th17, and T helper 1. When en- cious than either alone (Ishihara et al., 2017).
gaged with its ligands, TIM-3 is capable of Since TIM-3 is expressed on several T
suppressing Th17 and Th1 responses. In tu- cells, it could be a favorable target in cancer
mor tissues, there exists a significant associa- (Liu et al., 2014), having significant roles in
tion between the polymorphisms of TIM-3 innate immune cell-mediated antitumor im-
and PD-1 (programmed cell death 1) and the mune responses. PD-1 antibodies have been
expression level of TIM-3 and PD-1, such that reported to have a possible role in increasing
by administrating PD-1 and TIM-3 synergis- the expression of TIM-3 in lung cancer in in
tic promotion of tumor growth would be ob- vivo models, demonstrating that TIM-3 could
served (Topalian et al., 2012). The inhibitory be a marker of PD-1 blocking antibody re-
effects TIM-3 exerts on anti-tumor immunity sistance. However, the role that TIM-3 plays
are highlighted by the above mentioned pre- in cancer immunity needs further investiga-
clinical studies. tion. In fact, recent treatments targeting TIM-
Four ligands have been attributed to TIM- 3 might bring about a breakthrough in cancer
3, including phosphatidylserine (Epstein and therapy.
Philip, 1987), high-mobility group protein B1 Antitumor immunity could be enhanced
(HMGB1), carcinoembryonic antigen cell ad- by TIM-3 antibodies, since T helper 1 (TH1)
hesion molecule 1 (CEACAM-1), and galec- cell responses could be inhibited by TIM-3,
tin-9 (Gal-9), the latter of which was the first the ligand of which is galectin 9 (which itself
to be recognized (Wei et al., 2018). Through enjoys an upregulation in several cancer
negative regulation of T-cell immunity, TIM- types, such as breast cancer). The co-expres-
3/Gal-9 is capable of inhibiting cancer im- sion of TIM-3 with PD-1 on tumor-specific
munity. The connection between Gal-9 and CD8+ T cells has also been reported, and du-
TIM-3 IgV domain could terminate the im- ally blocking them considerably improves the
mune responses of T helper 1 (Th1). Also, in vitro cytokine production and proliferation
TIM-3 is capable of inhibiting T-cell immune of human T cells when stimulated via NY-
responses, and has been shown to have an as- ESO-1 or the cancer–testes antigen. In vivo,
sociation with immune exhaustion, inducing coordinately blocking TIM-3 and PD-1 has
chronic viral infection (Liu et al., 2013). been reported to be capable of enhancing tu-
Through the blockade of the TIM-3 pathway, mor rejection and antitumor immune re-
cancer immunity could be enhanced and the sponses under the same conditions in which
production of interferon-gamma (IFN-γ) single blocking brought about only modest ef-
could be increased in T cells (Wang et al., fects. Increased TIM‐3 on CD8+ T and CD4+
2011). The expression of CD8+ TIM-3+ T T cells has been reported in the peripheral
cells has been shown to have a correlation blood of OS patients, where high levels of
with PD-1 expression in vitro and in vivo. TIM-3 had a positive correlation with poor
Also, compared to TIM-3 negative CD8+ T prognosis, pathological tumor fracture, me-
cells, TIM-3 and PD-1 positive CD8+ T cells tastasis, and tumor stages (Liu et al., 2016a).
generate less IFN-γ 21. Interestingly, the IFN- Notably, the immune suppression is not di-
γ in peripheral NK cells could be increased by rectly mediated by the expression of TIM-3 in
using anti-TIM-3 antibodies. Not only could osteosarcoma patients. Instead, the interac-
LAG-3, TIM-3, or PD-1 improve the response tion between TIM-3+ T cells and Gal9-ex-
of T cells to tumor antigens, but they also en- pressing CD4+ CD25+ Tregs, naive CD4+ T
joy a synergistic function (Friedman et al., cells, and monocytes leads to the progressive
2016). The production of cytokines, including suppression of the responses of Th1 (Li et al.,
258EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
2017). In osteosarcoma tissues, the co-expres- killer (NK) cells (Li et al., 2017; Shang et al.,
sion of TIM-3 with several EMT-related pro- 2013), and on activated human CD8+ (cyto-
teins, such as Smad, Snail, Slug, and Vi- toxic = CTL) and CD4+ (helper = Th) T cells,
mentin has been documented, which makes a the latter of which could be detected within
contribution to the enhanced cancer cell inva- 24 h post in vitro stimulation. Moreover, the
siveness (Shang et al., 2013). Similarly, the expression of LAG-3 has been detected on
invasion of melanoma cells (B16) is promoted neurons (Wang et al., 2013) and B cells (Lui
by TIM-3 through the elevation of the activity and Davis, 2018), though not completely val-
of NF-κB, which leads to the metastasis of idated. In addition to being expressed on
melanoma (Wu et al., 2010). Feng et al. have membrane, LAG-3 is capable of lysosome
reported that transfection of MG-63 cells with storage, facilitating its prompt appearance on
the siRNA of TIM-3 is capable of inducing the surface of the cell following the activation
reduced expression of vimentin, E-cadherin, of T cells (Curdy et al., 2019).
and Snail, as well as NF-κB phosphorylation. There also exists a soluble form of LAG-
On this basis, it was assumed that TIM-3 is 3 (sLAG-3), which is released through shed-
capable of promoting EMT and inducing the ding at the surface of the cell, providing an
metastasis of osteosarcoma through the acti- extra layer of control and regulation of im-
vation of the NF-κB/Snail signaling pathway munity in the TME or periphery. Presumably,
(Feng and Guo, 2016). sLAG-3 is capable of impairing the differen-
tiation of monocytes in DCs or macrophages,
Lymphocyte-activation gene 3 (LAG-3) which produces APCs that eventually suffer
Discovered by Triebel et al almost 30 decreased immunostimulatory capacities (Hu
years ago in a transcript form, the expression et al., 2020). Also, sLAG-3 has been assessed
of which takes place via a cytokine IL-2–de- as a circulating biomarker in BC individuals
pendent natural killer cell line, LAG-3 en- who had hormone receptor (HR)-positive
codes a protein similar to co-receptor CD4. In metastatic disease, where diagnostically de-
fact, LAG-3 is the third inhibitory receptor tectable serum sLAG-3 had an association
pathway targeted clinically. The function of with a survival advantage (Wei et al., 2018).
LAG-3 includes the control of excessive acti- Similarly, these have been found in gastric
vation after persistent exposure to antigens in cancer recently (Duffy and Crown, 2019). To-
order to prevent autoimmunity (Koirala et al., gether, these evidence emphasize investigat-
2016; Wang et al., 2016b); nonetheless, it is ing sLAG-3 as a predictive or prognostic bi-
capable of making a contribution to the con- omarker of LAG-3-targeted therapies (Le
ditions under which T cells dysfunction in the Mercier et al., 2015). The action mechanism
tumor microenvironment (TME) (Liu et al., of the lymphocyte checkpoint protein LAG-3
2016a). Since there existed a homology to has always been relatively mysterious. How-
CD4, it was proposed that LAG-3 is capable ever, it seemingly operates at least in part
of binding to major histocompatibility com- through the recognition and suppression of re-
plex (MHC) class II, which was confirmed by sponses against MHC class II and stable com-
Triebel and colleagues through cell-binding plexes of peptides. Despite the fact that un-
assays. However, as opposed to CD4, the ex- known results exist with regards to LAG-3
pression of LAG-3 takes place on more than clinical studies, their rationale is founded on
CD4+ T cells; i.e. on myeloid cells, natural the data that suggest the co-targeting of LAG-
killer cells, and on activated CD8+ T cells 3 as a promising strategy in order to improve
(Lui and Davis, 2018). The receptors of LAG- the responses of immunotherapy in several
3 are expressed on murine plasmacytoid den- human tumor types. The co-expression of
dritic cells (pDC) constitutively (even though LAG-3 with other molecules of immune
not totally confirmed) (Wu et al., 2010), on a checkpoint, such as TIM-3, PD-L1 and PD-1
subclass of invariant NK T cells and natural
259EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
is well-documented, demonstrating the prom- sis in individuals suffering from cancer. Inter-
ising benefits of combinatorial immunothera- estingly, one of the direct targets of miR-124
pies that target several TME immunosuppres- in OS cells is B7-H3 (Wang et al., 2016a).
sive pathways could offer (Hu et al., 2020). The mRNA and protein levels of B7-H3 are
Nonetheless, it should first be demonstrated decreased as a result of miR-124 overexpres-
by safety data that sequentially or simultane- sion, which inhibits the activity of B7-H3 3′-
ously combining therapies would be both tol- UTR reporter. Using miR-124 mimics to treat
erable and feasible. Much attention has re- OS cells would enable the inhibition of the
cently been focused on LAG-3, which may growth and invasion of cells in vitro, which
belong to the second wave of immune check- could be abrogated through transfection with
point targets along with the receptors of the B7-H3 expression vector. It has been sug-
TIGIT and TIM-3, as it is expressed on tu- gested that miR-124 is potentially applicable
mor-infiltrating lymphocytes along with the as a novel onco-miRNA in OS through down-
immunoregulatory receptor PD-1 and is asso- regulating B7-H3 (Wang et al., 2016a).
ciated with T cell exhaustion (Le Mercier et Since the expression of B7-H7 takes place
al., 2015). in many osteosarcoma tumors and is linked to
poor survival and metastatic disease, it could
B7 family checkpoints be suggested that B7-H7 might enjoy a new
With respect to the perception of interplay immunosuppressive mechanism inside the tu-
between the immune system and cancer, re- mor microenvironment of the osteosarcoma.
cent agents have been developed in the recent It has been shown through the expression pat-
decade that target B7:CD28 family check- terns of novel B7 family molecules that re-
points. Ever since, the capability of targeting dundant mechanisms are probably used by
checkpoint regulators successfully has re- cancers for compromising immune attack,
sulted in the conductance of several clinical even though unique molecules often exist, in-
trials in which antibodies target the pathways cluding B7-H5 and B7-H6. It could be pre-
attributed to the B7 family members. Mem- dicted that the emphasis of immunotherapy
bers of the growing B7 family include B7-H7 would be laid on the effect of combined B7-
(or HHLA2), B7-H6 (or NCR3LG1), B7-H5 H ligand. Considering the osteosarcoma tu-
(or PD-1H, Dies1, GI24, or VISTA), B7-H4 mor, the expression of B7-H3 is inversely cor-
(or Vtcn1, B7x, or B7S1), B7-H3 (or CD276), related to TILs number, as well as promoting
B7-H2 (or ICOSL), B7-DC (or CD273 or PD- the cell invasion of osteosarcoma. Moreover,
L2), B7-H1 (or CD274 or PD-L1), CD86 (or significantly shorter survival and recurrence
B7.2), and CD80 (or B7.1). It has been docu- times have been reported in patients with high
mented that B7 molecules are capable of expression levels of B7-H3 (Wang et al.,
providing vital positive signals for stimulat- 2013). The effects of enoblituzumab are un-
ing and supporting the action of T cells, as der investigation on children with B7-H3-ex-
well as offering negative signals for control- pressing solid tumors, including desmoplastic
ling and suppressing the responses of T cells. small round cell tumors, Wilms’ tumor,
Poor outcomes have been reported to be Ewing sarcoma, osteosarcoma, rhabdomyosar-
significantly associated with the expression of coma, and neuroblastoma (NCT02982941).
B7-H3 in individuals suffering from breast
cancer, osteosarcoma (OS), cervical cancer, COMBINATIONAL STRATEGIES FOR
esophageal squamous cancer, gallbladder OPTIMIZING IMMUNE CHECK
cancer, CRC, prostate cancer, lung cancer, POINT INHIBITION IN
and RCC (Ni and Dong, 2017). Therefore, the OSTEOSARCOMA
expression of B7-H3 may provide an effective Immune checkpoint blockade (ICB),
and feasible means for predicting the progno- which targets PD-L1, PD-1, or CTLA-4 via
260EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
antibodies has resulted in unprecedented out- ovarian, and fibrosarcoma tumor mouse mod-
comes in previously incurable cancer patients els with trabectedin, the number of tumor site
(Zhao et al., 2018). However, long-term ben- macrophages and peripheral blood monocytes
efits are observed only in some patients. For were significantly reduced. It has been re-
the improvement of the number of cancer ported that trabectedin is capable of signifi-
types that respond and the response rate, com- cantly inhibiting the growth of the primary tu-
bination therapies have emerged, which target mor, and metastasis, of osteosarcoma through
other IRs as an instance (Curdy et al., 2019). exerting effects on both tumor and immune-
The members of the B7 family possess es- infiltrating cells, as well as exhibiting en-
sential co-stimulatory parts in the activation hanced therapeutic efficiency in combination
of T cells. B7-1a has been reported as an al- with PD-1–blocking antibody (Ratti et al.,
ternatively spliced form of B7-1. It was 2017). The efficiency of anti-CTLA-4 and
demonstrated by Nagamore et al. that extrin- anti-PD-L1 antibodies was evaluated by
sic (anti-CTLA-4 mAb) and intrinsic (lack of Takahashi et al. with X-ray irradiation in both
IgC-like domain in B7-1a) manipulations of distant and local impacts on osteosarcoma. It
the interactions of B7/CTLA-4 enhance the was shown that combining anti-CTLA-4 and
therapeutic efficiency of osteosarcoma vac- anti-PD-L1 antibodies (P1C4) with irradia-
cines that are based on B7, synergistically tion would enable exerting higher distant ef-
(Nagamori et al., 2002). Both in vivo and in fects as well as providing greater local anti-
vitro, the efficiency of osteosarcoma-reactive tumor efficiency for osteosarcoma. Adminis-
CTLs has been reported to be improved sig- trating P1C4 has been reported to be capable
nificantly through blocking the interaction of of producing a delay in the tumor growth on
PD-1/PD-L1, which results in reduced burden day 30 in 18 % of the mice. Conversely, com-
of the tumor as well as enhanced rate of sur- bination therapy has been shown to have pro-
vival in the osteosarcoma metastasis models duced stronger inhibition of the tumor, both in
(Lussier et al., 2015). Thus, combining the irradiated tumor and unirradiated tumor in
blockade of the interactions of PD-1/PD-L1 67 % of the mice. Also, lung metastases were
and adoptive CD8+ T cell would be beneficial greatly reduced (by 98 %) in the combina-
to pursue in the treatment of osteosarcomas. tional group, offering considerable survival
IFN-γ is capable of increasing efficacious benefits (Takahashi et al., 2017).
processing of antigens for MHC-mediated an-
tigen presentation, and thus enhancing im- RECOGNIZING AND MANAGING OF
mune responses in the tumor microenviron- IMMUNE CHECKPOINT BLOCKADE
ment (Boehm et al., 1997). However, combin- AVERSE EVENTS AND SIDE EFFECTS
ing IFN-γ with PD-1/PD-L1 blockade is yet Immune checkpoint blockade is responsi-
to be explored, as IFN-γ might be capable of ble for a wide range of dysimmune toxicity
simultaneously up-regulating PD-L1 expres- named as immune-related adverse events
sion in immune cells and peripheral tissues, (IRAEs), which include liver, gut, lung, endo-
and therefore suppressing the immune re- crine glands, skin and other tissues. These
sponses (Taube et al., 2012; Wang et al., IRAEs could possibly include the diarrhea in-
2016b). As a marine-derived chemotherapeu- duction or the appearance of Crohn’s disease,
tic, Trabectedin is being used clinically for autoimmune hepatitis, Hashimoto’s thyroidi-
treating soft-tissue sarcomas, or combined tis, hypophysitis and which can potentially be
with doxorubicin for the treatment of ovarian life-threatening complications in case unde-
cancer, as a second-line single-agent treat- tected or untreated (Thallinger et al., 2018). It
ment. However, monocytes and macrophages has been reported that such side effects can be
are also affected by the cytotoxic effects of recognized in 70 % of patients, though these
trabectedin. Following the treatment of lung, occur in only 20–30 % after treatment with
PD-L1 inhibitor (De Velasco et al., 2017). It
261EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
is known that rash and pruritus are the initial Surprisingly, it has been reported that var-
side effects of treatment process with anti ious tumor histologies such as renal cell, mel-
CTLA-4 and hypophysitis, diarrhea, colitis or anoma or NSCLC show different irAE phe-
liver toxicity tend to occur later. After PD-L1 nomena after treatment with PD-1 inhibitors.
inhibition, gastrointestinal and cutaneous are It was also shown that the immune cell infil-
the main IRAEs, but other phenomena such as trate, tumor microenvironment, neoantigen
hepatic, renal, endocrine and pulmonary are development and the response of adaptive im-
less common. Studies show that the combina- mune system could be impacted by histology,
tion of checkpoint inhibitors over the treat- which is a possible explanation for different
ment procedure could potentially lead to more toxicities (Khoja et al., 2017).
severe side effects, which are associated with Individuals with inflammatory disease are
the inhibition of CTLA-4 immune checkpoint more sensitive to irAEs over the treatment
(Thallinger et al., 2018). process with the inhibitors of immune check-
It is assumed that as immunotherapy in point. A research indicated that the pre-exist-
cancer can induce the response of tumor-di- ing AID was considerably linked with the risk
rected T‑cells by infiltration of T‑cells into of irAEs appearance in the treated patients
primary tumor or related metastases, it can with anti-PD-1 antibody. Other studies also
also lead to IRAEs in all types of tissues represented that the treatment of cancer with
(Pulluri et al., 2017). Treatment side effects anti-PD-1 antibodies is as an effective method
associated with immune checkpoint blockade for AID-free patients as it is for AID patients
differ in toxicity from cytotoxic agents. In (Danlos et al., 2018). As a practical approach,
conventional cytotoxics, the toxicity time can anti-PD-1 and anti-CTLA-4 antibodies are
also be delayed and not continue as a cyclical entering in cancer treatment, and the number
manner. The molecular mechanism of toxicity of individuals treated with such drugs will in-
is still to be completely known, but it may be crease exponentially in the future. Therefore,
heterogeneous among individuals even with it is necessary to have a close investigation on
the same toxic agent (Khoja et al., 2017). The pathophysiology and molecular mechanism
hyperactivation of T lymphocytes induced by of autoimmune diseases. Though irAEs can
immune checkpoint inhibitors can also gener- be limited by using steroids, the related im-
ate a particular response against the antigens munosuppression could interrupt the anti-
of tumor cells, causing to the tumor suppres- tumor response (Michot et al., 2016).
sion, though it has some side effects on health Nivolumab and ipilimumab are two well-
tissues known as "ontarget''. The lysis of cells known drugs for melanoma treatment, which
by CD8+ T lymphocytes is responsible for re- are accepted by the U.S. Food and Drug Ad-
leasing of different neoantigens such as tumor ministration, however, more than 60 % of pa-
auto-antigens or antigens in normal tissues. tients indicated grade 3 or 4 related side ef-
The phenomenon is known as "epitope fects. It was shown that near to 40 % of these
spreading'' which causes to diversification of patients are not able to continue this therapy
the associated T cell repertoire and conse- method because of significant adverse effects
quently suppressed immune tolerance that is (Larkin et al., 2015).
worsened following of Treg inhibition. More- Ishihara et al. reported that the anti-cancer
over, the Th1 and Th17 lymphocytes activa- effect of anti-PD-L1 and anti-CTLA-4 was re-
tion induced by immune checkpoint inhibitor markably increased by ECM-binding addi-
can increase the generation of pro-inflamma- tion. A further investigation showed that the
tory cytokines, including IL-17 and IFN-γ. PlGF-2123–144 conjugation with antibodies
These two molecular actions are responsible can increase its tissue retention. Also, a con-
for off-target toxicities (Gelao et al., 2014; siderable side effect reduction was approved
Yang et al., 2017). related to lower amount of antibody in
plasma. The peri-tumoral injections of anti-
262EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
PD-L1- PlGF-2123–144 plus anti-CTLA-4- sensitive due to the activation of immune re-
PlGF-2123–144 can induce the tumor-infil- actions and inhibition of immune evasion or
trating T cells, leading to the tumor suppres- suppression through ICIs immune check point
sion and increase the survival rate (Ishihara et inhibitors. The response of immune system to
al., 2017). immune check point inhibitor therapy is asso-
The engineering of ECM-binding anti- ciated with tumor-infiltrating lymphocytes
bodies is a potential approach that can be ap- (TILs) and active immune cells in the TME
plied for effective cancer therapy by blocking (Cogdill et al., 2017). It was confirmed that,
immune checkpoints. Totally, those patients in the responders, tumors represent high level
treated with immune checkpoint inhibitors, of neoantigen load and TILs, particularly ef-
every possible symptom should be considered fector cells, low levels of MDSC, high ratio
as a sign of irAE, and this should be informed of Teff to Treg, and raised secretion level of
to the patients. It is obvious that early detec- IFN-γ or other cytokines. However, in the
tion and treatment can inhibit the appearance non-responders, the TME includes high rate
of 4–5 toxicities (Friedman et al., 2016). of immunosuppressive cells, like, MDSCs
and Tregs, and very low rate of activated lym-
PREDICTIVE BIOMARKERS phocytes and NK cells (Darvin et al., 2018;
ASSOCIATED WITH IMMUNE De Angulo et al., 2008; Simeone et al., 2014).
CHECKPOINT INHIBITORS Furthermore, since PD-L1 has an im-
portant role in suppression of immunogenic-
The response of immune system to im-
ity and is known as a potential target for PD-
mune check point inhibitors is a complicated
L/PD-L1 antibodies, it was considered as a
process. Biomarkers that estimate the efficacy
predictive biomarker for such treatments. The
of immune check point inhibitors therapy and
individuals with PD-L1-positive tumors can
associated irAEs can be helpful in the patient
selection and treatment decision-making via achieve more advantage from PD-l/PD-L1
recognition of responders and non-respond- antibodies compared with those patients with
ers. PD-L1-negative tumors (Duffy and Crown,
The major concern in finding predictive 2019; Wei et al., 2018). A meta-analysis study
biomarkers is the wide range of cancer bi- which included 8 prospective randomized
omarker types and the genetic variation of pa- clinical trials (involved 4174 patients) with
tients (Nasiri et al., 2018; Valedkarimi et al., different form of cancer assessed the value of
2017). Biopsy studies of different sites of a PD-L1 evaluation for predicting benefit from
patient indicted a considerable variation of bi- PD-1/PD-L1 (Shen and Zhao, 2018). This
omarker which is associated with intra- study showed that the use of PD-1/PD-L1 in-
tumoral heterogeneity. Advanced research hibitors can remarkably increase the survival
will focus on development of combination bi- rate in both PD-L1 negative (HR, 0.80; 95 %
omarkers so as to estimate immune check CI, 0.71– 0.90) and PD-L1 positive [hazard
point inhibitor therapy results and limit irAEs ratio (HR), 0.66; 95 % CI, 0.59 – 0.74] com-
(Postow et al., 2018). Many researches on pared to conventional chemotherapy. How-
predictive biomarkers have focused on PD-L1 ever, the PD-1/PD-L1 antibodies were more
overexpression, immune cell infiltration, efficient for the patients with positive PD-L1
copy number alterations, peripheral blood rather than negative PD-L1 (Duffy and
analyses, SNPs, neoantigen, clonality, muta- Crown, 2019; Shen and Zhao, 2018).
tional landscape, mismatch-repair deficiency In a group of patients with advanced met-
and transcription factors (Darvin et al., 2018). astatic sarcoma, a study reported various par-
Growing evidence show that immune in- tial responses in osteosarcoma, dedifferenti-
flamed tumors have high tendency to re- ated chondrosarcoma and epithelioid sarcoma
sponse for immunotherapy. The studies indi- after treatment process with nivolumab
cated that the immune inflamed tissue is more
263EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
(Paoluzzi et al., 2016). Another study, how- checkpoint inhibitors in the activation of host
ever, revealed that the treatment of synovial immune responses. Selective anti-PD-L1,
sarcoma with anti-CTLA-4 antibody could anti-PD-1, and/or anti-CTLA-4 mAbs have
not induce the immunological antitumor re- brought about a revolution in treatment of
sponses in the studied patients (Maki et al., many types of cancer, among which lung can-
2013). Therefore, identification of bi- cer and melanoma have seen the greatest clin-
omarkers is a main step to improve the selec- ical efficacy. However, not in all patients is
tion process of sarcomas, which can respond immunotherapy fully effective, and thus se-
to the treatment based on immune checkpoint lecting biomarkers is required to optimize the
(Veenstra et al., 2018). treatment. With regards to OS, immunother-
Recently, the hyperprogression phenom- apy has been less effective. So far, despite the
ena was explained in a group of patients promising results from preclinical studies,
treated with anti-CTLA-4 antibodies and anti- solid evidence supporting the efficacy of im-
PD-1/PD-L1. In some cases, the growth of tu- munotherapy in these patients has not been
mor was increased after treatment of these in- provided. Better understanding the molecular
hibitors. This phenomena is mainly associ- mechanisms defining the OS immune compe-
ated with the mouse double minute (MDM) 2 tence is required for developing predictive bi-
and MDM4 gene amplification and possible omarkers as well as effective combination ap-
EGFR mutations (Champiat et al., 2017; Kato proaches, including chemotherapies or co-
et al., 2017). The MDM family members have stimulatory and targeted agents. One of the
been documented as key regulators of cancer main challenges in this regard would be the
protective responses. The appropriate func- identification of patients with particular tu-
tion of the MDM2 and MDM4 family is criti- mor and tumor infiltrating stroma functional
cal for normal development of breast tissue, and molecular features, among the heteroge-
but also for stabilizing genomic fidelity. As it neous OS spectrum, which could be treated by
is shown increased levels of the MDM2 and immunotherapy effectively.
MDM4 genes are associated with breast can-
cer (Haupt et al., 2017). In a comprehensive Authors’ contributions
statistical study, it was shown that MDM2 Vafa Meftahpour and Ali Aghebati-Ma-
amplification can be detected in most of sar- leki conceived the idea and provided the draft
coma cases (Momand et al., 1998). The am- of the manuscript. Ali Fotouhi participated in
plification of 12 chromosomes (12q13-15 re- literature survey. Elham Safarzadeh and Leili
gion) which includes MDM2 gene is a poten- Aghebati-Maleki provided inputs for the de-
tial hallmark of parosteal osteosarcoma, and sign and the final edition of the article. Leili
well-differentiated and dedifferentiated lipo- Aghebati-Maleki critically revised the manu-
sarcoma. Also, some other sarcomas indicate script. All authors read and approved the final
MDM2 amplification at a very low rate in manuscript.
cancer cells, including malignant peripheral
nerve sheath tumors and conventional osteo- Funding
sarcomas. These researches propose that the This study was supported by Research
treatment of sarcoma subtypes with the inhib- Vice-Chancellor at Tabriz University of Med-
itors of immune checkpoints must be care- ical Sciences, Iran [Grant No. 68036].
fully evaluated (Aleixo et al., 2009; Veenstra
et al., 2018). Declaration of interest
The authors declare that they have no
CONCLUSION conflict of interest.
Cancer immunotherapy has now turned
into an efficacious therapeutic approach as a
result of the elucidation of the role of immune
264EXCLI Journal 2022;21:250-268 – ISSN 1611-2156
Received: July 14, 2021, accepted: December 09, 2021, published: January 12, 2022
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