Cancer testis antigen PRAME: An anti‐cancer target with immunomodulatory potential

Abstract

PReferentially expressed Antigen in Melanoma (PRAME) is a cancer testis antigen with restricted expression in somatic tissues and re‐expression in poor prognostic solid tumours. PRAME has been extensively investigated as a target for immunotherapy, however, its role in modulating the anti‐tumour immune response remains largely unknown. Here, we show that PRAME tumour expression is associated with worse survival in the TCGA breast cancer cohort, particularly in immune‐unfavourable tumours. Using direct and indirect co‐culture models, we found that PRAME overexpressing MDA‐MB‐468 breast cancer cells inhibit T cell activation and cytolytic potential, which could be partly restored by silencing of PRAME. Furthermore, silencing of PRAME reduced expression of several immune checkpoints and their ligands, including PD‐1, LAG3, PD‐L1, CD86, Gal‐9 and VISTA. Interestingly, silencing of PRAME induced cancer cell killing to levels similar to anti‐PD‐L1 atezolizumab treatment. Comprehensive analysis of soluble inflammatory mediators and cancer cell expression of immune‐related genes showed that PRAME tumour expression can suppress the expression and secretion of multiple pro‐inflammatory cytokines, and mediators of T cell activation, differentiation and cytolysis. Together, our data indicate that targeting of PRAME offers a potential, novel dual therapeutic approach to specifically target tumour cells and regulate immune activation in the tumour microenvironment.

PRAME Immuno-Expression in Cutaneous Sebaceous Carcinoma: A Single Institutional Experience

“…In recent years, great research interest has been directed to the diagnostic, therapeutic and marker role of Preferentially expressed Antigen in Melanoma (PRAME) in the setting of various human neoplasms [ 1 , 2 ]. First discovered and described in 1997 by Ikeda H. et al, in an autologous T lymphocytes clone in a patient with metastatic cutaneous melanoma, PRAME has returned to the attention of researchers both in the context of possible immunotherapies [ 3 , 4 ] and its diagnostic role in lesions mainly of a melanocytic nature [ 5 , 6 ].…”

A panel of cancer testis antigens in pan squamous cell carcinomas: implication for biomarkers and therapeutic targets

“…Due to their expression pattern, CTAs have been attractive as cancer-speci c therapeutic targets. The immunogenicity of some CTAs was identi ed, suggesting that these CTAs could be applied in cancer immunotherapy [13,19,20]. Until now, several targeted immunotherapies for CTAs have been developed, and these immunotherapies have been tested in preclinical and early clinical trials [21].…”

“…PRAME is frequently expressed in various solid tumors, such as head and neck cancer and non-small-cell lung cancer NSCLC [11,12]. PRAMEbased vaccines and adoptive T cell therapies have shown a favorable safety pro le and e cient induction of potent immune responses in tumors [13]. Kita-Kyushu Lung Cancer antigen-1 (KK-LC-1), also known as CT83, is expressed in different types of cancers.…”

Biology of Cancer-Testis Antigens and Their Therapeutic Implications in Cancer

“…Another extensively investigated target CTA for immunotherapeutic strategies is PRAME. Most studies on PRAME as an immune environment modulator implicate a negative correlation between the expressions of PRAME and antigen-presenting molecules as well as immune checkpoint molecules such as PD-1, LAG3 (lymphocyte-activation gene 3), PD-L1(programmed death-ligand 1), CD86 (cluster of differentiation 86), Gal-9 (galectin-9) and VISTA (V-domain Ig suppressor of T-cell activation) [ 185 , 186 , 187 , 188 ]. This implies that PRAME expression may be involved in immune escape mechanisms during carcinogenesis and may potentially indicate an immune cold tumour environment.…”

“…Thus, modulation of PRAME expression is considered a viable strategy to improve the efficacy of immune checkpoint inhibitors in cancers. Interestingly, PRAME tumour expression was shown to suppress the expression and secretion of multiple proinflammatory cytokines and mediators of T-cell activation, differentiation and cytolysis during inflammation [ 185 ], further highlighting the role of PRAME in regulating immune activation in the tumour microenvironment (TME). Of note, a recent study by Takata et al demonstrated that in patients with diffuse large B-cell lymphoma (DLBCL), PRAME -deleted tumours showed cytotoxic T-cell immune escape and were associated with cold tumour microenvironments with the enhancer of zeste homolog 2–activating (EZH2-activating) mutations suppressing PRAME expression.…”