Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer

Immune checkpoint inhibitors have emerged as a potent new class of anticancer therapy. They have changed the treatment landscape for a range of tumors, particularly those with a high mutational load. To date, however, modest results have been observed in breast cancer, where tumors are rarely hypermutated. Because BRCA1 -associated tumors frequently exhibit a triple-negative phenotype with extensive lymphocyte infiltration, we explored their mutational load, immune profile, and response to checkpoint inhibition in a Brca1 -deficient tumor model. BRCA1 -mutated triple-negative breast cancers (TNBCs) exhibited an increased somatic mutational load and greater numbers of tumor-infiltrating lymphocytes, with increased expression of immunomodulatory genes including PDCD1 ( PD-1 ) and CTLA4 , when compared to TNBCs from BRCA1 –wild-type patients. Cisplatin treatment combined with dual anti–programmed death-1 and anti–cytotoxic T lymphocyte–associated antigen 4 therapy substantially augmented antitumor immunity in Brca1 -deficient mice, resulting in an avid systemic and intratumoral immune response. This response involved enhanced dendritic cell activation, reduced suppressive FOXP3 + regulatory T cells, and concomitant increase in the activation of tumor-infiltrating cytotoxic CD8 + and CD4 + T cells, characterized by the induction of polyfunctional cytokine-producing T cells. Dual (but not single) checkpoint blockade together with cisplatin profoundly attenuated the growth of Brca1 -deficient tumors in vivo and improved survival. These findings provide a rationale for clinical studies of combined immune checkpoint blockade in BRCA1 -associated TNBC.