Abstract 4696: Targeting CSF1R+ macrophages to synergize immune checkpoint therapy in SCCA-mediated radioresistant cervical cancer

Abstract Tumor-associated factors released by cancer cells can promote immune suppression and tolerance to radiation or immune therapy. Squamous cell carcinoma antigen (SCCA) is a tumor-associated antigen released by cancer cells. In cervical cancer, elevated pre-treatment SCCA in the serum is seen in 28-88% of patients and these patients are more likely to experience treatment resistance and recurrence. The poor prognosis for patients with elevated SCCA shows the need for improve treatment strategies. Here, we aim to understand the mechanism of action of circulating SCCA to tumor progression and response to radiotherapy. Using sequencing analysis of paired pre- versus on-treatment biopsies, we found that patients with elevated serum SCCA had increased macrophages expressing immunosuppressive features and T-cell immune checkpoints, inversely correlated with inflammatory signaling and radiation-induced interferon-stimulated gene expression. The supplement of SCCA protein (rSCCA) to the media during in vitro macrophage differentiation promotes anti-inflammatory cytokines and gene expression. Peritoneal macrophages isolated from mice treated with intra-peritoneal rSCCA expressed high M2-associated markers and functional inhibition of T cell activation. Moreover, we found that mouse tumors engineered to express SCCA with a signal peptide promoting extracellular secretion displayed increased CSF1R+ TAM infiltration and decreased T cell activation, associated with reduced response to combined radiation and anti-PDL1 treatment. Giving the findings, we hypothesized that targeting TAMs in tumors with elevated SCCA is imperative. We further demonstrated that tumor-bearing mice showed improved response to radiation and immune checkpoint therapy when receiving concurrent CSF1R blockade, abolishing the protective effect of high circulating SCCA. Our results suggest that blockade of CSF1R signaling or other myeloid-targeting therapeutics will optimize response to radiation and PD-L1 blockade in cervical cancer, particularly those with high circulating SCCA. Citation Format: Liyun Chen, Eric Liu, Victoria Shi, Marlene L. Campos Guerrero, Jasmin Yang, Abhay Singh, Matthew Inkman, Jin Zhang, Julie Schwarz, Stephanie Markovina. Targeting CSF1R+ macrophages to synergize immune checkpoint therapy in SCCA-mediated radioresistant cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4696.