Combined immune checkpoint blockade as a therapeutic strategy for <i>BRCA1</i> -mutated breast cancer

Abstract

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 <i>BRCA1</i>-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 <i>Brca1</i>-deficient tumor model. <i>BRCA1</i>-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 <i>PDCD1</i> (<i>PD-1</i>) and <i>CTLA4</i>, when compared to TNBCs from <i>BRCA1</i>-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 <i>Brca1</i>-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 <i>Brca1</i>-deficient tumors in vivo and improved survival. These findings provide a rationale for clinical studies of combined immune checkpoint blockade in <i>BRCA1</i>-associated TNBC.