Zhang Xiaowei, Zhao Yang, Chen Xu
General Surgery Ward, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China.
Intensive Medical Ward, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China.
Transl Oncol. 2024 Nov;49:102113. doi: 10.1016/j.tranon.2024.102113. Epub 2024 Aug 30.
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.
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.
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.
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.
胃癌（GC）仍然是一项重大的全球健康挑战，预后较差，部分原因是其具有逃避免疫系统的能力。细胞外基质（ECM），尤其是胶原蛋白，在肿瘤免疫逃逸中起关键作用，但其潜在机制尚未完全明确。本研究通过激活IL4I1-AHR信号通路，探讨胶原蛋白ECM在促进胃癌免疫逃逸中的作用。
我们在3D胶原蛋白凝胶中培养胃癌细胞，并通过与HER2特异性CAR-T细胞共培养来评估其免疫逃逸能力。分析了IL4I1及其代谢产物的表达，并探讨了整合素αvβ1在介导胶原蛋白作用中的作用。此外，还在体外和体内评估了IL4I1诱导的AHR激活对CAR-T细胞耗竭的影响。
我们发现，在胶原蛋白上培养的胃癌细胞对CAR-T细胞的细胞毒性具有更高的抗性，这与CAR-T细胞上免疫检查点分子的上调和效应细胞因子的下调有关。这与IL4I1表达增加有关，而IL4I1表达在3D胶原蛋白环境中通过整合素αvβ1信号进一步诱导。IL4I1代谢产物，尤其是犬尿氨酸（KynA），通过激活AHR途径促进CAR-T细胞耗竭，导致细胞毒性降低和肿瘤生长抑制减弱。
我们的研究揭示了一种新机制，即胶原蛋白ECM通过激活IL4I1-AHR信号促进胃癌免疫逃逸，导致CAR-T细胞耗竭。靶向该途径可能会提高CAR-T细胞疗法在胃癌中的疗效。
