Journal Article

456 Alcohol use reduces the efficacy of anti-PD1 immunotherapy by disrupting T cell mediated anti-tumor immunity

Garness Jason, Coleman, Leon, Vincent, Benjamin G, Gilley, Kristen

2025

Overview

BackgroundImmune checkpoint inhibition (ICI) has led to improved response rates in metastatic cancer, however only a subset of patients respond. The exact reason(s) for lack of response are an active area of research, and environmental exposures that alter systemic immunity might impact ICI efficacy. Alcohol exposure is a common lifestyle factor with known detrimental effects on adaptive immune cell function. Therefore, we hypothesized that alcohol intake would negatively impact ICI efficacy.MethodsWe performed a retrospective study of 238 patients treated with ICI therapy for lung, bladder, melanoma, or head and neck cancer, associating survival with drinking history and tumor transcriptomic features. To better understand the immunomodulatory effects of alcohol exposure, we established murine models of lung (LN4K1) and bladder (MB49) tumors in which mice received either 2.5g/kg (moderate dose) or 5g/kg (binge dose) of ethanol pre-treatment for 5 weeks (5 days/week, i.g.) prior to tumor injection. At day 8, 11, and 14 mice were treated with anti-PD1 (10 ug/kg), and tumor size was monitored. Additionally, we performed flow cytometry to evaluate leukocyte phenotypes in the tumor microenvironment and spleen on day 11 post-tumor. We also used RNA sequencing and functional assays (MTT and EliSPOT) of OT-1 T cells to better understand ethanol’s impact on T cell function.ResultsAlcohol exposure was associated with reduced survival in human cancer patients treated with anti-PD-1 therapy (Lung HR: 1.7, Bladder HR: 2.27). In the murine lung model, ethanol significantly reduced the efficacy of the ICI regimen, worsening survival from 58 days to 86 days. In the bladder model, both moderate and binge alcohol decreased survival post-immunotherapy from 89% to near 30%. In murine bladder tumors, we found significant decreases in the number of CD4+ and CD8+ T cells. We also found that CD4+ differentiation was altered away from a Th1 phenotype in favor of Th2 and Th17 phenotypes. In the spleen, FoxP3 and IL10 expression were significantly increased in both CD4+ and CD8+ T cells, suggesting that alcohol induced regulatory T cell phenotypes. In addition, CD8 T cells exposed to ethanol showed reduced capacity for IFN stimulation (via EliSPOT) and cytotoxicity (via MTT assay).ConclusionsAlcohol exposure was associated with decreased efficacy of ICI therapy. These studies implicate alcohol-induced T cell dysfunction through loss of T cells in the tumoral space, impaired effector T cell differentiation, and loss of CD8+ T cell cytotoxicity.Ethics ApprovalAll animal studies were approved by University of North Carolina IUCAC under protocol #23-230. Human data usage was approved by University of North Carolina IRB under protocol LCCC1727.

• Publisher: BMJ Publishing Group LTD
• Subject: Alcohol / Bladder / Cytotoxicity / Ethanol / Immunotherapy / Lymphocytes / Tumors