Abstract B007: CD163+ tumor-associated macrophage evasion contributes radiation resistance and poor prognosis in estrogen receptor-negative breast cancer
Authors: Subhajit Ghosh, Suryakant Niture, Jerry Jaboin, Danushka Seneviratne
Journal: Clinical Cancer Research (2025)

Abstract Patients with estrogen receptor-negative (ER-) breast cancer demonstrate worse clinical outcomes and poor prognosis from post-mastectomy radiation therapy (PM-RT) than those with ER-positive (ER+) breast tumors. RT modulates the tumor microenvironment (TME) dynamic and its impact on immune evasion and resistance remains unclear. In this prospective study, we explore the role of CD163, a scavenger receptor protein primarily expressed in monocytes and M2-like tumor-associated macrophages (TAM), in driving local and systemic immunosuppression and immune evasion after RT, particularly in ER- tumors. For this, ER- and ER+ biopsy breast tumor tissues (n=45) and peripheral blood samples were collected from pre-RT and post-RT exposed patients. A tumor transcriptomic profiling was performed using the NanoString platform, and peripheral blood mononuclear cells and plasma cytokines levels were analyzed through flow cytometry. Patient-derived monocytes were sorted, polarized into M2C macrophages, and co-cultured with healthy T cells to assess the immunosuppressive role of M2C-CD163, with and without the anti-CD163 monoclonal antibody (OR2805). Further, an orthotopic murine breast cancer model (4T1; ER-/TNBC cells) was developed to confirm M2-CD163's role in immunosuppression following RT and its influence on the response to checkpoint immunotherapy. The Cancer Genome Atlas (TCGA) analysis revealed that higher expression of CD163 transcripts associated with poor overall survival in ER- but not in ER+ breast cancer patients, and our data suggest that RT significantly increases CD163, the transcriptomic signature of TAM markers (MRC1, ATF3, DUSP1, PTPRC, DAB2) as well as upregulates several transcription factors (STAT1, STAT2, CEBPB, NFKB1A) that involved in TAM-mediated immunosuppression. Intriguingly, RT-induced immune evasion to ER- breast tumors, elevates CD163 in the plasma and increases monocyte plasticity toward an M2-like phenotype. These monocyte-derived macrophages suppressed T cell activity, highlighting the strong immunosuppressive potential of monocytes from irradiated ER- breast tumors. Inhibition of CD163 by monoclonal antibody reversed the RT-induced immunosuppression, reprogramming monocytes/macrophages to a pro-inflammatory M1 phenotype and restoring T cell activity. In addition, RT promoted myeloid cell differentiation into CD163+M2-like macrophages, leading to immunosuppressive changes within the tumor and systemic circulation in mice in vivo. Pharmacologic depletion of CD163+ macrophages in combination with RT improved overall survival and enhanced tumor responsiveness to checkpoint immunotherapy. In conclusion, our data suggest CD163 is a key mediator of radiation-induced immunosuppression in ER- breast cancer, and pharmacological targeting of CD163 in aggressive and advanced ER- breast tumors may improve radiation response and patient outcomes. Citation Format: Subhajit Ghosh, Suryakant Niture, Jerry Jaboin, Danushka Seneviratne. CD163+ tumor-associated macrophage evasion contributes radiation resistance and poor prognosis in estrogen receptor-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B007.