Dataset Information

Targeting immunosuppressive macrophages overcomes PARP-inhibitor resistance in BRCA1-associated triple-negative breast cancer

ABSTRACT: 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. 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. 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. 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte, Macrophage

DISEASE(S): Breast Cancer

SUBMITTER: Jennifer Guerriero

LAB HEAD: Jennifer L. Guerriero, PhD

PROVIDER: PXD015804 | Pride | 2021-03-25

REPOSITORIES: Pride

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Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer.

Mehta Anita K AK Cheney Emily M EM Hartl Christina A CA Pantelidou Constantia C Oliwa Madisson M Castrillon Jessica A JA Lin Jia-Ren JR Hurst Katie E KE de Oliveira Taveira Mateus M Johnson Nathan T NT Oldham William M WM Kalocsay Marian M Berberich Matthew J MJ Boswell Sarah A SA Kothari Aditi A Johnson Shawn S Dillon Deborah A DA Lipschitz Mikel M Rodig Scott S Santagata Sandro S Garber Judy E JE Tung Nadine N Yélamos José J Thaxton Jessica E JE Mittendorf Elizabeth A EA Sorger Peter K PK Shapiro Geoffrey I GI Guerriero Jennifer L JL

Nature cancer 20201214 1

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. 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 m ...[more]

PMID: 33738458

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