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

Abstract

Despite 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.

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

“…Alcohol consumption induces ALDH2 and subsequently upregulates PD-L1 expression in CRC, thereby protecting it from immune surveillance. Therefore, the combination of ALDH2 inhibition and anti-PD-1 therapy enhances the anti-tumor immunity and can be used as a novel strategy to enhance the efficacy of ICB in CRC patients, especially those who consume alcohol [ 216 ].…”

A novel fatty acid metabolism‐related gene signature predicts the prognosis, tumor immune properties, and immunotherapy response of colon adenocarcinoma patients

“…ALDH2 is an enzyme involved in ethanol metabolism and acetaldehyde breakdown, such as 4‐hydroxykingenal and malondialdehyde, to acetate. In recent years, multiple studies have demonstrated pro‐colorectal cancer consequences of ALDH2 activation, which directly regulates metabolic and inflammatory responses 34 . The carnitine palmitoyl transferase system (CPTs) regulates fatty acid β‐oxidation.…”

“…In recent years, multiple studies have demonstrated pro-colorectal cancer consequences of ALDH2 activation, which directly regulates metabolic and inflammatory responses. 34 The carnitine palmitoyl transferase system (CPTs) regulates fatty acid βoxidation. In the outer mitochondrial membrane, CPT1 is situated, while CPT2 is located in the inner mitochondrial membrane.…”

ALDH2 gene rs671 G > a polymorphism and the risk of colorectal cancer: A hospital‐based study

“… 63 Moreover, ALDH2 is linked to autophagy regulation in some diseases, and it was speculated that autophagy is one of the mechanisms that ALDH2 uses to regulate tumor occurrence and development. 64 , 65 In addition, ALDH2 indirectly regulates the immune system due to its role in aldehydes metabolism and acetaldehyde adducts, 66 , 67 and it may also be one of the mechanisms by which ALDH2 is involved in tumor development.…”