837 Targeting a CD36-dependent macrophage immunometabolic program enhances PARP inhibitor response in BRCA-associated TNBC
Year: 2026
Type: conference-abstract
Abstract: Background Although Poly (ADP-ribose) polymerase inhibitors (PARPi) induce tumor DNA damage, activating cGAS-STING signaling and enhance tumor immunogenicity, and immune infiltration, we have demonstrated that, in BRCA-deficient triple-negative breast cancer (TNBC), PARPi simultaneously promotes the accumulation of immunosuppressive tumor-associated macrophages (TAMs), characterized by CSF1R, PD-L1 and CD36, a key lipid scavenger receptor involved in lipid accumulation in macrophages and therapy resistance. However, the metabolic mechanisms driving TAM-mediated immune suppression and PARPi resistance remain poorly defined.Methods Paired baseline and 1-month on-treatment biopsies were obtained from 12 patients with BRCA1/2-mutated breast cancer receiving talazoparib monotherapy (TALAVE trial- NCT03964532), including 5 with gBRCA1, 6 with gBRCA2, and 1 with sBRCA2 mutations. The samples were analyzed using NanoString IO360TM, Digital Spatial Profiling (DSP), and multiplexed immunofluorescence (CyCIF) to characterize metabolic and immune changes induced by PARPi. In parallel, BRCA1-deficient tumor-bearing mice (K14-Cre/Brca1f/f/Trp53f/f) were treated with the PARPi Olaparib or vehicle and tumors were analyzed by bulk RNA sequencing, flow cytometry, and metabolomics. Mechanistic studies evaluated IL-34/M-CSF signaling via CSF1R as a driver of CD36-dependent lipid accumulation in bone marrow-derived macrophages (BMDMs). CD36 was targeted using Sulfosuccinimidyl oleate (SSO), anti-CD36 antibodies, or myeloid-specific Cd36 deletion (LysM-Cre+/-/Cd36fl/fl) in combination with PARPi.Results PARPi therapy increased infiltration of TAMs and exhausted CD8 T cells together with marked tumor metabolic remodeling. Spatial transcriptomic and multiplexed immunofluorescence analyses demonstrated enrichment of lipid metabolic pathways, including cholesterol transport and regulation of lipid metabolism, particularly within TAM-rich regions. Similarly, in a BRCA1-deficient TNBC mouse model, PARPi induced broad immunometabolic remodeling characterized by increased myeloid and CD8 + T-cell infiltration and enhanced expression of genes involved in lipid transport, and fatty acid metabolism. PARPi promoted accumulation of CD36+PD-L1+ TAMs with increased lipid uptake capacity. Moreover, metabolomic profiling showed increased phospholipid and triglyceride species within tumors and tumor interstitial fluid following PARPi, whereas TAM depletion with anti-CSF1R prevented lipid accumulation, identifying TAMs as key mediators of a lipid-rich tumor microenvironment. Importantly, lipid species enriched after PARPi treatment directly suppressed CD8+T-cell effector function by reducing granzyme B expression. Mechanistically, PARPi induced tumor expression of IL-34 and M-CSF. These cytokines, alone or in combination, increased expression of CD36. Therapeutically, CD36 inhibition using SSO, anti-CD36 antibodies, or myeloid-specific Cd36 deletion significantly enhanced antitumor responses and prolonged survival in combination with PARPi.Conclusions Targeting CD36-mediated lipid uptake restored antitumor immune responses and enhanced PARPi therapeutic activity, identifying TAM lipid metabolism as a promising therapeutic vulnerability to overcome PARPi resistance.Trial Registration NCT03964532Ethics Approval The present study was approved by BWH CMM IACUC, protocol number is 2020N000142 and by Dana-Farber Cancer Institute, protocol number is 20–627. Study drugs were provided by Pfizer, as part of an alliance between Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).
Authors: Carlos Wagner S Wanderley, Daniel E Michaud, Kiran Kurmi, Adam Nelson, Kenichi Shimada, Alexander P Gottlieb, Gabriella Antonellis, Kelly F Zheng, Anita Mehta, Madeline G Townsend, Xue Geng, Candace Mainor, Mei Wei, Julie Collins, Paula R Pohlmann, Arielle L Keeke, Hongkun Wang, Claudine Isaacs, Filipa Lynce, Geoffrey I Shapiro, Jessica E Thaxton, Marcia C Haigis, Jennifer L Guerriero
Institutions: Brigham and Women's Hospital, University of Miami, Harvard University, Dana-Farber Cancer Institute, Georgetown University, MedStar Georgetown University Hospital, University of Utah, AstraZeneca (United States), The University of Texas MD Anderson Cancer Center, Georgetown University Medical Center, Georgetown Lombardi Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225181756