860 Targeting immunosuppressive macrophages overcomes PARP-inhibitor resistance in BRCA1-associated triple-negative breast cancer. (10th December 2020)

• Record Type: Journal Article
• Authors: Mehta, Anita; Cheney, Emily; Hartl, Christina; Pantelidou, Constantia; Oliwa, Madison; Castrillon, Jessica; Lin, Jia-Ren; Hurst, Katie; Taveira, Mateus de Oliveira; Johnson, Nathan; Oldham, William; Kalocsay, Marian; Berberich, Matthew; Boswell, Sarah; Kothari, Aditi; Johnson, Shawn; Dillon, Deborah; Lipschitz, Mikel; Rodig, Scott; Santagata, Sandro; Garber, Judy; Tung, Nadine; Yélamos, José; Thaxton, Jessica; Mittendorf, Elizabeth; Sorger, Peter; Shapiro, Geoffrey; Guerriero, Jennifer
• Is Part Of: Journal for immunotherapy of cancer. Volume 8(2020)Supplement 3
• Page Start: A512
• Page End: A512
• Publication Date: 2020-12-10
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-SITC2020.0860
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Methods: Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Results: Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Conclusions: Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.