Alcohol use reduces the efficacy of anti-PD1 immunotherapy by disrupting anti-tumor immunity

Abstract

Immune checkpoint inhibition (ICI) has improved clinical outcomes for certain patients with cancer. However, only a minority of patients have durable responses with underlying causes of differential immune responses across individuals often being unknown. Lifestyle exposures impact immune function and may subsequently alter the response to ICI. Alcohol use is common among cancer patients with known detrimental effects on adaptive immune function. However, its impact on ICI efficacy remains unknown. To determine if alcohol impacts ICI therapies, we performed a retrospective assessment of outcomes for patients receiving anti-PD1 ICI across tumor types and employed preclinical mouse models of ICI for lung and bladder cancer. Alcohol use reduced ICI efficacy in human patients treated with anti-PD1 for lung and bladder cancer (HR [~]2.0) as well as in murine models ICI in lung (LN4K1) and bladder (MB49) cancer. Alcohol reduced tumoral T cell numbers, promoting less productive Th2 and Th17 CD4+ phenotypes intratumorally and regulatory phenotypes in the periphery. In both rodent and ex-vivo human T cells, alcohol disrupted T cell activation and effector functions. Thus, alcohol use negatively impacts ICI efficacy warranting alcohol cessation for this patient population.