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

Nolan, E; Savas, P; Policheni, AN; Darcy, PK; Vaillant, F; Mintoff, CP; Dushyanthen, S; Mansour, M; Pang, JB; Fox, SB; Kathleen Cuningham Foundation Consortium for Research into Familial Breast, Cancer; Perou, CM; Visvader, JE; Gray, DHD; Loi, S; Lindeman, GJ

Author(s): Nolan, E; Savas, P; Policheni, AN; Darcy, PK; Vaillant, F; Mintoff, CP; Dushyanthen, S; Mansour, M; Pang, JB; Fox, SB; Kathleen Cuningham Foundation Consortium for Research into Familial Breast, Cancer; Perou, CM; Visvader, JE; Gray, DHD; Loi, S; Lindeman, GJ;
Details: Publication Year 2017-06-07,Volume 9,Issue #393,Page eaal4922
Journal Title: Science Translational Medicine
Publication Type: Journal Article
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.
Publisher: AAAS
Research Division(s): Stem Cells And Cancer; Molecular Genetics Of Cancer
PubMed ID: 28592566
Link To PubMed Central Version: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28592566/
Publisher's Version: https://doi.org/10.1126/scitranslmed.aal4922
NHMRC Grants: NHMRC/1016701, NHMRC/1040978, NHMRC/1078763, NHMRC/1037230, NHMRC/1102742, NHMRC/1078730,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-06-26 02:15:28

Last Modified: 2018-07-04 09:19:29