Abstract 3434: Spatially resolved multi-omic profiling reveals BRCA-dependent immune remodeling during PARP inhibition and PD-L1 blockade

Abstract Background: PARP inhibitors (PARPi) induce synthetic lethality in BRCA1/2-mutant (BRCA-MUT) tumors and can activate DNA-damage-linked immune pathways. The TALAVE study (NCT03964532) examined the combination of the PARPi (talazoparib) with PD-L1 blockade (avelumab). Here we evaluated spatially resolved immune signaling and remodeling in response to talazoparib alone and with avelumab. Methods: 24 patients with advanced HER2-negative breast cancer (12 BRCA-MUT, 12 BRCA-WT) received talazoparib then talazoparib + avelumab. Serial biopsies (baseline, post-PARPi [BX2], post-combination [BX3]) underwent transcriptomic, spatial protein, and multiplex IF. BRCA-dependent TME remodeling and cellular neighborhood (CN) shifts were assessed. Results: BRCA-MUT tumors showed 83% objective response and 100% clinical benefit, whereas BRCA-WT tumors exhibited minimal activity. BRCA-MUT tumors became fragmented with increased immune activity, while BRCA-WT tumors remained compact and immunosuppressed. γH2AX and pTBK1 were spatially co-expressed and sustained in BRCA-MUT tumors during treatment but declined in BRCA-WT tumors. BRCA-MUT tumors displayed enrichment of CD8+ T cells and CD163+ macrophages after PARPi, whereas CD4+ T cells and CD68+CD163+ macrophages were depleted in BRCA-WT tumors. PD-1+ CD8+ T cells were strongly linked to local CD4+ T cell density, and PD-1+ frequency in CD8+ T cells correlated with longer PFS at baseline and BX3 in BRCA-MUT but not BRCA-WT tumors.CN analysis revealed CD4+ and CD8+ enriched neighborhoods with intermediate PD-1 expression that expanded after therapy in BRCA-MUT but not BRCA-WT tumors, and these CNs lacked PD-L1+ cells. Between BX2 and BX3, BRCA-MUT tumors sustained immune activity but showed no further T cell activation or infiltration. Spatial mapping identified three PD-L1+ CN types: (1) T cell-dense niches with high PD-1/PD-L1 and γH2AX-pTBK1 activity enriched only at baseline, largely lost after PARPi; (2) macrophage-T cell mixtures that were depleted during therapy; and (3) PD-L1+ dying tumor cells lacking pTBK1 activity and T cell engagement. Across contexts, PD-L1 was either lost before PD-L1 blockade or confined to regions isolated from T cells, leaving little opportunity to reinvigorate T cells. Conclusions: PARP inhibition reshaped the TME of BRCA-MUT tumors by inducing tumor fragmentation, sustaining γH2AX-pTBK1 signaling, and restoring CD4+ and CD163+ immune cells, whereas BRCA-WT tumors remained structurally intact and immunosuppressed. PD-1+ T cells localized to PD-L1-negative neighborhoods, and PD-L1+ tumor/myeloid cells were rapidly lost or confined to dying, immune-excluded regions, limiting the impact of PD-L1 blockade. Although PARPi re-engaged T cell programs in BRCA-MUT tumors, strategies beyond PD-L1 inhibition will be required to further enhance T cell infiltration and activation. Citation Format: Kenichi Shimada, Filipa Lynce, Claudine Isaacs, Xue Geng, Edward T. Richardson, Candace Mainor, Mei Wei, Julie M. Collins, Paula R. Pohlmann, Arielle L. Heeke, Kelly F. Zheng, Madeline Townsend, Lauren M. Sloat, Jane Staunton, Stuart J. Schnitt, Hongkun Wang, Joan S. Brugge, Geoffrey I. Shapiro, Jennifer L. Guerriero. Spatially resolved multi-omic profiling reveals BRCA-dependent immune remodeling during PARP inhibition and PD-L1 blockade [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 3434.