Abstract 7125: Distinct CD8+T cell subsets in advanced melanoma patients with liver metastasis

Abstract Background: Liver metastases (LM) in melanoma are linked to poor prognosis, reduced immunotherapy efficacy, and survival, likely due to a suppressive liver immune microenvironment. We hypothesized that LM induces distinct, detectable immune changes in blood and tumor biopsies, supported by our prior preclinical findings. We set to immunophenotype tissues from stage IV melanoma patients to identify systemic and local immune changes, uncover immune tolerance mechanisms, and define biomarkers distinguishing LM-associated suppression. These insights aim to inform strategies to overcome liver-specific immune tolerance, enhance immunotherapy predictability and efficacy, and improve clinical outcomes for LM+ melanoma patients. Methods: Peripheral blood and tumor samples were longitudinally collected from advanced melanoma patients pre, during, and post treatment clinic visits and/or surgeries. Clinical data, including imaging, treatment, and bloodwork, were obtained. Stage IV patients were stratified into two cohorts: LM+ and LM-. Fresh tumor and blood tissues were immunophenotyped by 12-24 color flow cytometry. Results: In tumor specimens, ICOS expression on CD8+ subsets were significantly reduced in LM+ patients. Three distinct CD8+ T cell subsets were identified correlating with LM status. In peripheral blood, LM+ patients exhibited significantly lower frequencies of HLA-DR+CD8+ and HLA-DR+CD11c+CD11b-CD8+ subsets compared to LM- patients, while the CD11c+CD11b-CD8+ subset was significantly higher. Similarly, in tumor tissue, LM+ patients showed an increased frequency of CD11c+CD11b-CD8+ subset and a decreased frequency of HLA-DR+CD8+ subset. These observations underscore potential functional differences in immunity between LM+ and LM- patients. These subsets warrant further studies on the immune dynamics of melanoma LM. Conclusions: Our parallel immunophenotyping of melanoma clinical samples is a foundational step towards developing predictive/prognostic biomarkers to distinguish between LM+ and LM- patients and their outcomes. We identified distinct T-cell subsets with differential representation between cohorts, with reduced expression of ICOS in CD8+ subsets and enrichment of CD11c+CD11b-CD8+ subset in LM+ patients. The functional roles of these subsets require further investigation. Given the immune-regulatory nature of the liver tumor microenvironment and clinical manifestations in LM+ patients, we hypothesize that the CD11c+CD11b-CD8+ subset exhibits a regulatory phenotype, contributing to immune suppression and tumor progression. We aim to characterize this subset at phenotypic, transcriptional, and functional levels, elucidating its role in LM-mediated immune modulation. These findings will inform the development of novel biomarkers and therapeutic strategies for melanoma patients with metastatic disease. Citation Format: Shao Tao, Zang Han, Asha Bunyan, Adil Daud, Ajay Maker, James Lee. Distinct CD8+T cell subsets in advanced melanoma patients with liver metastasis [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 7125.