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Sci Transl Med. 2017 Jun 7;9(393). pii: eaal4922. doi: 10.1126/scitranslmed.aal4922.

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

Author information

1
Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
2
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
3
Division of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
4
The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
5
Molecular Genetics of Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
6
Immunotherapy Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
7
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
8
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
9
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
10
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
11
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
12
Division of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. sherene.loi@petermac.org lindeman@wehi.edu.au.
13
Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. sherene.loi@petermac.org lindeman@wehi.edu.au.
14
Parkville Integrated Familial Cancer Centre, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Victoria, Australia.
15
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.

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.

PMID:
28592566
PMCID:
PMC5822709
DOI:
10.1126/scitranslmed.aal4922
[Indexed for MEDLINE]
Free PMC Article

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