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

SIMPLE SUMMARY: Soft tissue sarcomas are a group of malignant tumors developing from connective tissues in different parts of the human body. In the face of limited options for systemic therapy, immunotherapeutic approaches are currently being explored. In this context, cancer testis antigens (CTAs) are potential targets for cancer immunotherapy due to tumor-specific patterns of expression and high immunogenicity. We, therefore, aimed to describe the expression of three CTAs, PRAME, NY-ESO-1, and SSX2, and analyze their prognostic value in a large cohort of high-risk soft tissue sarcomas with long-term follow-up. Our results show sarcoma subtype-specific patterns of CTA expression and we demonstrate an association of CTAs with overall survival, especially for PRAME. Our results provide support for future trials investigating CTA-directed immunotherapy in eligible patients with various sarcoma subtypes and they may help establish CTAs as diagnostic tools in soft tissue sarcoma. ABSTRACT: (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.