1541P - Presence of tumor-specific cytolytic T cells in human primary breast carcinoma: consequences for immunotherapy

Abstract

Immunotherapy through stimulatory antibodies targeting the CTLA-4 or PD-1 pathways has a demonstrated clinical efficacy in a fraction of patients with various cancers. It is likely that the main immune effectors of these therapies are CD8+ cytolytic T lymphocytes (CTL) recognizing tumor-specific antigens. Highly antigenic tumors such as metastatic melanomas are often immunogenic, i.e. they stimulate spontaneous anti-tumor CTL responses. This immunogenicity, of which the presence of tumor-infiltrating T cells (TILs) is probably a surrogate marker, might be a predictive marker for clinical benefit to immunostimulatory antibodies. The immunogenicity of primary breast carcinomas for CD8+ T cells has not been studied, but the amounts of TILs have been positively correlated with patients' survival. Here we wished to obtain evidence for the presence of tumor-specific CD8+ T cells in TILs from primary breast carcinomas. From 5 tumors (2 ER+/HER2-, 2 ER+/HER2+, 1 ER-/HER2-) we isolated TILs and derived a random set of ±100 CD8+ T cell clones that we screened for recognition of candidate tumor-specific antigenic peptides selected through tumor exome sequencing and gene expression profiling. These peptides were encoded either by mutated genes or by cancer-germline genes. For 4 tumors, we screened 61-142 T cell clonotypes for recognition of 23-61 candidate mutated peptides, without any positive result. For the last tumor (ER+/HER2-), 6 out of 57 T cell clonotypes recognized 4 out of 109 candidate mutated peptides but not the corresponding wild-type peptides. This tumor contained more mutations than the other four, and displayed microsatellite instability. Some human primary breast carcinomas are immunogenic, as one tumor contained at least 10% of tumor-specific cells among the CD8+ TILs. Our observation corroborates the association between high mutation burden and CTL response to mutated tumor antigens. The presence of tumor-specific CD8+ suggests that the corresponding patient could benefit from the currently used immunostimulatory antibodies.