Cancer testis antigens in sarcoma: Expression, function and immunotherapeutic application

Wei, Ran; Dean, Dylan C.; Thanindratarn, Pichaya; Hornicek, Francis J.; W, Guo; Duan, Zhenfeng

doi:10.1016/j.canlet.2019.10.024

Cited by 30 publications

(22 citation statements)

References 85 publications

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“…CTAs are expressed in STS ( 68 ), and three main groups are of interest: melanoma-associated antigen gene (MAGE), preferentially expressed antigen of melanoma (PRAME) and New York esophageal squamous cell carcinoma 1 (NY-ESO-1). Interestingly, their expression is not associated with complex genomics, but seems correlated to a hypomethylated genomic profile, thus underlining the rationale of associating epigenetic and immunotherapeutic approaches in STS ( 69 ). On the whole, around 20% and 12% of all STS respectively express NY-ESO-1 and MAGE-A4, possibly conferring them a better prognosis ( 70 ).…”

Section: The Tumor Microenvironment Of Soft-tissue Sarcomasmentioning

confidence: 99%

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

et al. 2021

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Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.

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Section: The Tumor Microenvironment Of Soft-tissue Sarcomasmentioning

confidence: 99%

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

et al. 2021

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“…Several CTAs, like MAGE, NY-ESO-1, and PRAME, are expressed in different sarcoma subtypes, such as synovial sarcoma [5][6][7][8][9][10][11], myxoid/round cell liposarcoma [6,[11][12][13][14][15][16], and other soft tissues sarcomas. CTAs can be highly immunogenic and are considered potential targets for immunotherapy of cancer [17].…”

Section: Introductionmentioning

confidence: 99%

Cancer Testis Antigens and Immunotherapy: Expression of PRAME Is Associated with Prognosis in Soft Tissue Sarcoma

Albertsmeier

Altendorf-Hofmann

Lindner

et al. 2020

Cancers

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(1) Background: PRAME, NY-ESO-1, and SSX2 are cancer testis antigens (CTAs), which are expressed in testicular germ cells with re-expression in numerous cancer types. Their ability to elicit humoral and cellular immune responses have rendered them promising targets for cancer immunotherapy, but they have never been studied in a large and well-characterised cohort of soft tissue sarcomas (STS). (2) Methods: On a protein level, we examined PRAME, NY-ESO-1, and SSX2 expression in tumour tissues of 249 high-risk STS using immunohistochemistry. We correlated expression levels with clinicopathological parameters including tumour-infiltrating lymphocyte (TIL) counts, grading, and long-term survival. (3) Results: Expression of PRAME, NY-ESO-1, and SSX2 was observed in 25 (10%), 19 (8%), and 11 (4%) of 249 specimens with distinct patterns for histo-subtypes. Expression of PRAME was associated with shorter patient survival (p = 0.005) and higher grade (G2 vs. G3, p = 0.001), while NY-ESO-1 expression was correlated with more favourable survival (p = 0.037) and lower grade (G2 vs. G3, p = 0.029). Both PRAME and NY-ESO-1 expression were more frequent in STS with low TIL counts. In multivariate analysis, high PRAME and low SSX2 expression levels as well as metastatic disease and non-radical resections were independent predictors of shorter overall survival. (4) Conclusions: CTAs PRAME, NY-ESO-1, and SSX2 show distinct expression patterns in different STS subtypes. These results demonstrate their prognostic relevance and may guide future immunotherapeutic approaches in STS.

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“…Recently, CTAs have drawn attention due to their irreplaceable role in tumorigenesis. Therapeutically, since antigens derived from CTAs are highly recognizable by T lymphocytes, they are capable of generating a potent antitumor immune response 30) . In addition, MAGE-1, NY-ESO-1, and MAGE-C2 have been shown to induce a spontaneous immune response in an autologous host 21,31) .…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we demonstrated that the frequent expression of MAGE-1, NY-ESO1, MAGE-C2 and SCP-1 CTAs represent potential immunological targets in ACC patients. It is clear that combined CTA-targeted immunotherapy represents the most promising method for the synergistic effects and reduction of T cell exhaustion and counter regulation 30) . Further verification with additional experiments and clinical trials are required to explore optional combination therapy.…”

Section: Discussionmentioning

confidence: 99%

Expression of Cancer-testis Antigens in Adenoid Cystic Carcinoma of the Salivary Glands Correlates with Clinical Outcomes

Liang

Fang

Chen

et al. 2021

J. Hard Tissue Biology.

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This study aimed to explore the expression and clinicopathological significance of CTAs MAGE-1, NY-ESO-1, MAGE-C2 and SCP-1 in adenoid cystic carcinoma (ACC). Immunohistochemistry was used to detect their expressions in 70 cases of ACC, and in 6 healthy tumor-adjacent salivary glands. The correlation between the expressions of the four CTAs, clinical and pathological features, and patients' overall survival (OS) were analyzed. Of the 70 ACC cases, strong staining was observed in 43 (61.4%) for MAGE-1, 14 (20%) for NY-ESO-1, 9 (12.9%) for SCP-1, and 6 (8.6%) for MAGE-C2. We also found some significant correlations between the CTAs expression and clinicopathological parameters, for example, MAGE-1 and tumor size, NY-ESO-1 and distant metastasis, MAGE-C2 and tumor site, SCP-1 and age, SCP-1 and histopathological types (P < 0.05). Patients with any single CTAs positive staining showed a similar OS compared to those with negative staining, however patients with strong expression (score 6-7) of MAGE-C2 showed a significantly reduced OS compared to those scored 0-5 (P < 0.05). There was no OS difference between patients expressing simultaneously any 2 of the 4 CTAs and those with negative expression or those expressing only one of the 2 CTAs. Similar results were found in patients expressing at least 3 CTAs compared with patients expressing less than 3 CTAs. However, patients with the four CTAs co-expression had a substantially reduced mean survival time of 131.8 months compared with 176.5 months in patients with at least one CTA negative (P < 0.05). In conclusion, a significant fraction of patients with ACC showed expression of MAGE-1, NY-ESO-1, MAGE-C2 and SCP-1, indicating these CTAs might represent potential antigens for cancer vaccines. In addition, MAGE-C2 may be an important prognostic marker of ACC.

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Cancer testis antigens in sarcoma: Expression, function and immunotherapeutic application

Cited by 30 publications

References 85 publications

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

Cancer Testis Antigens and Immunotherapy: Expression of PRAME Is Associated with Prognosis in Soft Tissue Sarcoma

Expression of Cancer-testis Antigens in Adenoid Cystic Carcinoma of the Salivary Glands Correlates with Clinical Outcomes

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