PO.IM02.05 · 免疫学
胞啃作用主导的 CLDN18.2 修饰型 CD8+ T 细胞通过葡萄糖代谢重编程诱导的细胞毒性削弱及系统性免疫衰老级联驱动胰腺癌进展
Trogocytosis-orchestrated CLDN18.2-dressed CD8 + T cells drive pancreatic cancer progression via glucose metabolic reprogramming-induced cytotoxicity debilitation and systematic immune senescence-cascade
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：CLDN18.2 是胃肠道癌症中已确立的治疗靶点；然而，相当一部分 CLDN18.2 阳性肿瘤对治疗无反应。尽管其在上皮细胞中的表达已被广泛研究，但 CLDN18.2 在免疫细胞中的表达、功能作用及调控机制仍未被探索。
结果：挑战 CLDN18.2 仅表达于上皮细胞的传统观念，我们首次报道肿瘤内 CD8+ T 细胞上存在 CLDN18.2 蛋白。肿瘤来源的 CLDN18.2 通过 ALCAM-CD6 介导的胞啃作用转移至 T 细胞，这一过程需要细胞间接触。其获得与 PDAC 中的不良预后及免疫治疗耐药相关。在 T 细胞中，被胞啃获得的 CLDN18.2 直接结合 beta-catenin，募集 CK1alpha/GSK3beta 复合物，促进 beta-catenin 磷酸化、被 beta-TrCP 识别及随后的泛素-蛋白酶体降解，从而减弱 Wnt/beta-catenin 信号通路。这种抑制诱导以葡萄糖摄取和糖酵解活性降低为特征的代谢重编程，导致 T 细胞增殖、活化、granzyme B 和 IFN-gamma 产生及整体细胞毒功能受损。此外，CLDN18.2+ CD8+ T 细胞通过 CXCL12/CXCR4 信号增强了向骨髓的归巢，分泌 IL-1alpha，促进造血干细胞的髓系偏向（扩增 GMP/MDP 群体），并促成系统性免疫衰老，共同抑制抗肿瘤免疫。基于 CLDN18.2 与 beta-catenin 的相互作用，我们开发了一种肽抑制剂 PC18.1，它可破坏该信号轴、逆转糖酵解抑制、恢复效应 T 细胞功能、减轻免疫衰老，并与抗 PD-1 治疗协同，在体内抑制 PDAC 进展。
结论：我们的研究结果揭示 CLDN18.2 是一种经胞啃作用由肿瘤向 T 细胞传递的代谢性免疫检查点：CLDN18.2 的转移抑制 beta-catenin 信号、抑制糖酵解、损害 T 细胞细胞毒性并诱导系统性免疫衰老。靶向 CLDN18.2-beta-catenin 界面（例如使用 PC18.1）可重新激活 T 细胞功能，是改善 CLDN18.2 高表达实体瘤治疗结局的有前景策略。
查看英文原文 English abstract
Background: CLDN18.2 is an established therapeutic target in gastrointestinal cancers; however, a significant proportion of CLDN18.2-positive tumors do not respond to treatment. While its expression has been extensively studied in epithelial cells, the expression, functional role, and regulatory mechanisms of CLDN18.2 in immune cells remain unexplored.
Results: Challenging the conventional paradigm that CLDN18.2 is exclusively epithelial, we report for the first time the presence of CLDN18.2 protein on CD8⁺ T cells within tumors. Tumor-derived CLDN18.2 is transferred to T cells via ALCAM-CD6-mediated trogocytosis, a process requiring cell-cell contact. Its acquisition correlates with poor prognosis and resistance to immunotherapy in PDAC. In T cells, trogocytosed CLDN18.2 binds directly to beta-catenin, recruits the CK1alpha/GSK3beta complex, and promotes beta-catenin phosphorylation, recognition by beta-TrCP, and subsequent ubiquitin-proteasome degradation, thereby attenuating Wnt/beta-catenin signaling. This suppression induces metabolic reprogramming characterized by reduced glucose uptake and glycolytic activity, resulting in impaired T-cell proliferation, activation, granzyme B and IFN-gamma production, and overall cytotoxic function. Furthermore, CLDN18.2⁺ CD8⁺ T cells exhibit enhanced homing to the bone marrow via CXCL12/CXCR4 signaling, secrete IL-1alpha, promote hematopoietic stem cell myeloid skewing (expanding GMP/MDP populations), and contribute to systemic immune senescence, collectively dampening antitumor immunity. Based on the CLDN18.2-beta-catenin interaction, we developed a peptide inhibitor, PC18.1, which disrupts this signaling axis, reverses glycolytic suppression, restores effector T-cell function, mitigates immune senescence, and synergizes with anti-PD-1 therapy to inhibit PDAC progression in vivo.
Conclusions: Our findings reveal CLDN18.2 as a metabolic immune checkpoint transmitted via trogocytosis from tumor to T cells: transfer of CLDN18.2 inhibits beta-catenin signaling, suppresses glycolysis, compromises T-cell cytotoxicity, and induces systemic immune senescence. Therapeutic targeting of the CLDN18.2-beta-catenin interface-for instance, with PC18.1-reinvigorates T-cell function and represents a promising strategy for improving treatment outcomes in CLDN18.2-high solid tumors.
利益披露 Disclosure
J. Yan, None.