Collagen extracellular matrix promotes gastric cancer immune evasion by activating IL4I1-AHR signaling

Abstract

Background

Gastric cancer (GC) remains a significant global health challenge with poor prognosis, partly due to its ability to evade the immune system. The extracellular matrix (ECM), particularly collagen, plays a crucial role in tumor immune evasion, but the underlying mechanisms are not fully understood. This study investigates the role of collagen ECM in promoting immune evasion in gastric cancer by activating the IL4I1-AHR signaling pathway.

Methods

We cultured gastric cancer cells in 3D collagen gels and assessed their immune evasion capabilities by co-culturing with HER2-specific CAR-T cells. The expression of IL4I1 and its metabolites was analyzed, and the role of integrin αvβ1 in mediating the effects of collagen was explored. Additionally, the impact of IL4I1-induced AHR activation on CAR-T cell exhaustion was evaluated, both in vitro and in vivo.

Results

We found that gastric cancer cells cultured on collagen exhibited increased resistance to CAR-T cell cytotoxicity, which was associated with upregulated immune checkpoint molecules and downregulated effector cytokines on CAR-T cells. This was linked to increased IL4I1 expression, which was further induced by integrin αvβ1 signaling within the 3D collagen environment. IL4I1 metabolites, particularly KynA, promoted CAR-T cell exhaustion by activating the AHR pathway, leading to decreased cytotoxicity and tumor growth inhibition.

Conclusions

Our study reveals a novel mechanism by which the collagen ECM facilitates immune evasion in gastric cancer through the activation of IL4I1-AHR signaling, contributing to CAR-T cell exhaustion. Targeting this pathway could potentially enhance the efficacy of CAR-T cell therapy in gastric cancer.