Abstract 7133: Combined anti-CSF-1R and anti-TIM-3 overcome macrophage-mediated mechanisms of PARP inhibitor (PARPi) resistance in BRCA1-associated triple negative breast cancer

Abstract Background: Poly (ADP-Ribose) polymerase inhibitors (PARPi) have improved outcomes for BRCA-associated triple negative breast cancer (TNBC); however, resistance develops, resulting in lack of durable responses. Our prior work demonstrated that PARPi activates cGAS/STING signaling, driving CD8+ T-cell recruitment, essential for tumor clearance. These studies led to clinical trials testing PARPi plus immune checkpoint blockade (ICB). However, clinical trials demonstrated no benefit compared to PARPi monotherapy, indicating T-cells in the tumor microenvironment (TME) are inhibited. We previously showed that PARPi induce suppressive tumor-associated macrophages (TAMs) which contribute to PARPi resistance. Removing TAMs with anti-CSF-1R therapy significantly enhanced overall survival (OS) when combined with PARPi and is now being tested in clinical trials (NCT03604692). Here, we test if ICB can enhance the CSF-1R +PARPi combination in both treatment naïve and PARPi-resistant tumors. Methods: Mice bearing naïve or PARPi-resistant BRCA1-deficient TNBC (K14-Cre;Brca1f/f;Trp53f/f) tumors were treated with PARPi ± CSF-1R inhibition (CSF-1Ri) ± ICB and followed for tumor size and OS. Flow cytometry was employed to define immune mechanisms of response. Results: In PARPi-naïve tumors, PARPi + CSF-1Ri significantly increased OS compared to PARPi monotherapy. The combination of PARPi + CSF-1Ri + anti-PD-1 led to a modest improvement in efficacy compared to PARPi + CSF-1Ri treatment. In contrast, the addition of anti-TIM3 to PARPi + CSF-1Ri resulted in durable therapeutic benefit, with a significant increase in OS compared to PARPi + CSF-1Ri. The combination of PARPi + CSF-1Ri + anti-TIM-3 significantly increased CD8+ T-cell infiltration, granzyme B production, and reduction in Tregs indicating an increased anti-tumor immune response. Additionally, anti-TIM-3 induced a pro-inflammatory phenotype in TAMs. In PARPi-resistant tumors TAMs expressed higher levels of CSF-1R compared to PARPi-naïve tumors. Additionally, PARPi-resistant tumors had increased infiltration of Tregs, and higher expression of PD-1 on T-cells, strongly indicating an increased immunosuppressive TME. In PARPi-resistant tumors, anti-CSF-1R therapy restored PARPi efficacy and significantly increased OS. Furthermore, addition of anti-TIM-3 to the anti-CSF-1R + PARPi combination significantly increased OS in PARPi-resistant tumors, whereas anti-PD-1 did not enhance therapy efficacy. Conclusion: PARPi-resistant tumors have increased T-cell exhaustion and infiltration of immunosuppressive TAMs. Importantly, our data shows that targeting TAMs through the CSF-1R axes can overcome acquired PARPi resistance, which can be further enhanced with anti-TIM3 therapy, defining a novel strategy addressing a critical unmet medical need. Citation Format: Adam Nelson, Anita K. Mehta, Madeline G. Townsend, Daniel E. Michaud, Madisson Oliwa, Kelly F. Zheng, Carlos W. Wanderley, Alex P. Gottlieb, Kenichi Shimada, Patrice A. Lee, Nicholas A. Saccomano, Filipa Lynce, Nabihah Tayob, Geoffrey I. Shapiro, Jennifer L. Guerriero. Combined anti-CSF-1R and anti-TIM-3 overcome macrophage-mediated mechanisms of PARP inhibitor (PARPi) resistance in BRCA1-associated triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7133.