Research ArticleCancer

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

See allHide authors and affiliations

Science Translational Medicine  07 Jun 2017:
Vol. 9, Issue 393, eaal4922
DOI: 10.1126/scitranslmed.aal4922

You are currently viewing the abstract.

View Full Text

Bringing out the neoantigens

Immune checkpoint inhibitors are becoming increasingly popular and successful for the treatment of cancer, but they have not gained much ground in breast cancer so far. Tumors with high mutation rates resulting in more neoantigens should be particularly susceptible to immunotherapy, but even breast cancers with mutations in BRCA1, a DNA repair gene, have thus far not been found to be overly responsive to checkpoint inhibition alone. Nolan et al. found, however, that these tumors may be susceptible to treatment if pushed enough. By treating BRCA1-mutant breast cancers with cisplatin to increase their mutational load and then combining drugs targeting two different immune checkpoint inhibitors, the authors achieved promising results in mouse models, suggesting that a similar approach may also work for patients.

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 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.

View Full Text