期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 9, 期 393, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aal4922
关键词
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资金
- Australian National Health and Medical Research Council (NHMRC) [1016701, 1040978, 1078763]
- NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS)
- Victorian State Government through the Victorian Cancer Agency and Operational Infrastructure Support
- Breast Cancer Research Foundation (New York)
- Qualtrough Cancer Research Fund
- Joan Marshall Breast Cancer Research Fund
- Australian Cancer Research Foundation
- Cancer Council Victoria Scholarship
- Cancer Therapeutics CRC Top-Up Scholarship
- NHMRC Fellowship [1041828, 1079329, 1078730]
- NCI Breast SPORE program [P50-CA58223-09A1, RO1-CA195740-01]
- NHMRC Australia Fellowship [1037230]
- NHMRC Elizabeth Blackburn Research Fellowship [1102742]
- NHMRC Career Development Fellowship-2 [1090236]
- John Colebatch Cancer Council Victoria Clinical Fellowship
- National Breast Cancer Foundation [IF-12-06] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1090236, 1079329] Funding Source: NHMRC
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.
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