Abstract A069: Radiotherapy remodels the tumor microenvironment via a TREM2-associated macrophage program that can be therapeutically targeted with TREM2 blockade

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Abstract The prostate cancer (PCa) tumor microenvironment (TME) is enriched in myeloid cells that drive progression and therapy resistance. Tumor-associated macrophages (TAM) can promote tumor growth by suppressing antitumor immunity. We have previously shown that stereotactic body radiotherapy (SBRT) induces inflammatory remodeling of the PCa TME with enrichment of a population of radiation-induced TREM2+ TAM. Herein, we characterize the immunological impact of TREM2-expressing TAM on intratumoral T-cell function and explore the therapeutic potential of TREM2 blockade in the context of radiotherapy. We performed 10x scRNA-seq on prostatectomy specimens from high-risk PCa patients treated with preoperative SBRT or non-irradiated controls. THP-1 and bone marrow–derived macrophages (BMDMs) were used to assess radiation-induced immune response. In vivo studies in C57BL/6 mice bearing PTEN-/-SPOPmutCHD1del organoid-derived or B6CaP flank tumors assessed immune changes after SBRT. Anti-TREM2 mAb treatment +/- SBRT was used to evaluate the immune remodeling of the TME. scRNA-seq analysis of human samples revealed enrichment of a myeloid cluster expressing a damage-associated macrophage signature (Trem2, Apoe, Spp1, Lgals3) in SBRT-treated versus controls (35.6% vs 5.7%). Irradiation increased TREM2 expression in BMDMs (p<0.01) and THP-1 cells under M0 and TAM-like conditions. When co-cultured with irradiated (vs. non-irradiated) BMDM-M0 cells, CD8+ T-cells demonstrate a decrease in CD8+ T-cell proliferation (p<0.012) and IFN-γ production (p<0.0005). Further, CD8+ T-cells co-cultured with TREM2hi TAMs (vs. TREM2lo) from irradiated organoid PCa tumors demonstrated a higher proportion of T-cells expressing Tim-3+ (p<0.001) and PD-1+ (p<0.01), suggesting that TREM2hi TAMs may induce a terminally exhausted phenotype in CD8+ T-cells. In vivo studies demonstrated that SBRT reduces tumor volume and was associated with a corresponding increase in intra-tumoral density of TREM2+ TAMs and FoxP3+ regulatory T-cells (Tregs) (p<0.008) in both organoid-derived PCa and B6CaP flank models. Tumor lysate from irradiated tumors demonstrated elevated soluble TREM2 (p < 0.028) and TGF-β1 (p < 0.034) levels. scRNA-seq of irradiated and non-irradiated organoid-derived flank tumors confirmed a radiation-induced anti-inflammatory TAM program (Arg1, Mrc1, Msr1, Tgfbi), corroborating our human PCa data. The combination of TREM2 blockade and SBRT remodeled the TME with a reduction in the density of intratumoral FoxP3+ Tregs and reduced Treg:Teff ratio as well as fewer TAMs expressing Arg1 and TGF-β1, collectively suggesting abrogation of SBRT-induced immunosuppression. Our findings in irradiated human PCa and subsequent validation studies in preclinical PCa models suggest that SBRT promotes a TREM2-driven anti-inflammatory macrophage program that remodels the immune TME. TREM2 blockade represents a potential strategy to reverse immune suppression and promote anti-tumor immunity when combined with SBRT. Citation Format: Janny A. Villa-Pulgarin, Un In Chan, Jiansheng Wu, Fabio Socciarelli, Jeffrey Kraynak, Sidney Wolfe, Hubert Pakula, Luigi Marchionni, Francesca Khani, Massimo Loda, Himanshu Nagar, Christopher Barbieri, Ariel E. Marciscano. Radiotherapy remodels the tumor microenvironment via a TREM2-associated macrophage program that can be therapeutically targeted with TREM2 blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A069.

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