PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer
- PMID: 30540933
- PMCID: PMC6366450
- DOI: 10.1016/j.celrep.2018.11.054
PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer
Abstract
PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients.
Keywords: BRCA deficiency; GEMM; PARP inhibition; PD-1 blockade; STING; immune response; immunotherapy; ovarian cancer; targeted therapy.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
DECLARATION OF INTERESTS
J.F.L. has been on advisory boards for Clovis and Mersana Therapeutics. G.J.F. has patents on the PD-1 pathway licensed by Bristol-Myers Squibb, Roche, Merck, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, DAKO, and Novartis and has served on advisory boards for Roche, Bristol-Myers Squibb, Xios, and Origimed. T.M.R. has a consulting relationship with Novartis, is a founder of Crimson Biotech and Geode Therapeutics, and is a member of the corporate boards of iKang Healthcare, Crimson Biotech, and Geode Therapeutics. P.A.K. has served on the advisory boards of Vertex, Pfizer, Merck, and AstraZeneca. U.A.M. has served on the advisory boards of 2X Oncology, Fujifilm, Immunogen, Mersana, Geneos, and Merck. L.D., Q.W., H.-J.K., and J.J.Z. are co-inventors of DFCI 2409.001 (DFS-203.60). J.J.Z. is a founder and board director of Crimson Biotech and Geode Therapeutics.
Figures




References
-
- Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack JL, Erle DJ, Barczak A, Rosenblum MD, Daud A, Barber DL, et al. (2014). Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 938. - PubMed
-
- Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, and Helleday T (2005). Specific killing of BRCA2-deficienttumourswith inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous