Investigation of the Cancer Testis Antigen Prame as a Novel Regulator of Immune Evasion in Triple Negative Breast Cancer

Background

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Preferentially expressed antigen in melanoma (PRAME), a member of the testis antigen family is found to be re-expressed in TNBC and thus serves as a prognostic factor and promising immunotherapeutic target. Moreover, PRAME was found to be a member of the leucine rich repeat (LRR) family proteins and to be upregulated by IFN-a or pathogen associated molecular patterns (PAMPs). Taken together, PRAME has a potential role in the anti-tumor immune response.

Aim

This study was conducted to evaluate the immune modulation of PRAME-overexpressing TNBC cells and whether CXCL12 (previously found to be downregulated in the PRAME overexpressing cell line) is implicated in the process.

Methods

Various in vitro experiments were conducted including direct and indirect co-culture assays, chemotaxis and migration assays to evaluate the role of PRAME in T-cell chemotaxis, T-cell activation and cytolytic activity.

Results

We demonstrated that PRAME overexpression in TNBC could reduce Tcell activation and cytolytic activity, but had no effect on T-cell migratory capability. We observed downregulation of several immune-related genes, involved in T-cell activation and to a lesser extent chemotaxis (gene ontology analysis). Focused analysis of CXCL12 suggested that it was not a major player in PRAME-mediated immune modulation.

Conclusion

Given the inhibiting effect of PRAME on T-cell activity and cytotoxicity, PRAME-targeted therapy might be beneficial for TNBC patients whether possibly combined with immune checkpoint inhibitors to provide more effective treatment and more favorable outcomes in TNBC patients.