Aldehyde Dehydrogenase 2 Mediates Alcohol‐Induced Colorectal Cancer Immune Escape through Stabilizing PD‐L1 Expression

Advanced Science - Tập 8 Số 10 - 2021
Hong Zhang1, Yuhui Xia1, Fang Wang1, Min Luo1, Ke Yang1, Shaobo Liang1, Sainan An1, Shaocong Wu1, Chuan Yang1, Da Chen1, Meng Xu1, Muyan Cai1, Kenneth K.W. To2, Liwu Fu1
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
2School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

Tóm tắt

AbstractDespite the great success of immunotherapy in a small subset of cancer patients, most colorectal cancer (CRC) patients do not respond to programmed cell death receptor 1 (PD‐1) blockade immunotherapy. There is an urgent medical need to elucidate how cancer cells evade immune response and to develop novel means to boost the efficacy of immune checkpoint inhibitors. In this study, alcohol induces ligand programmed cell death receptor 1 (PD‐L1) expression of CRC cells in vitro and in vivo. Alcohol exposure is shown to induce aldehyde dehydrogenase 2 (ALDH2) expression that is a crucial enzyme involved in alcohol metabolism, and low level of lymphocytes infiltration in the murine CRC model and patients. Intriguingly, ALDH2 and PD‐L1 protein expression are positively correlated in tumor tissues from the CRC patients. Mechanistically, ALDH2 stabilizes PD‐L1 protein expression by physically interacting with the intracellular segment of PD‐L1 and inhibiting its proteasome‐dependent degradation mediated by an E3 ubiquitin ligase Speckle Type POZ Protein (SPOP). Importantly, inhibition of ALDH2 reduces PD‐L1 protein in CRC cells and promotes tumor‐infiltrating T cells (TILs) infiltration, presumably leading to the significant potentiation of anti‐PD‐1 antibody efficacy in a mouse CT26 CRC model. The findings highlight a crucial role played by ALDH2 to facilitate alcohol‐mediated tumor escape from immunity surveillance and promote tumor progression.

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Advanced Science

Tập 8 Số 10

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