Trogocytosis-orchestrated CLDN18.2-dressed CD8+ T cells drive pancreatic cancer progression via glucose metabolic reprogramming-induced cytotoxicity debilitation and systematic immune senescence-cascade
Presenter: Jingrui Yan, MD;PhD Session: Tumor-induced Immune Suppression Time: 4/22/2026 9:00:00 AM → 4/22/2026 12:00:00 PM
Authors
Jingrui Yan 1 , Tianxing Zhou 2 , Jun Yu 1 , Jihui Hao 1 1 Tianjin Medical Univ. Cancer Inst. & Hospital, Tianjin, China, 2 Tianjin Medical Univ. Cancer Inst. & Hospital, He Xi Qu, China
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 β-catenin, recruits the CK1α/GSK3β complex, and promotes β-catenin phosphorylation, recognition by β-TrCP, and subsequent ubiquitin-proteasome degradation, thereby attenuating Wnt/β-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-γ production, and overall cytotoxic function. Furthermore, CLDN18.2⁺ CD8⁺ T cells exhibit enhanced homing to the bone marrow via CXCL12/CXCR4 signaling, secrete IL-1α, 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-β-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 β-catenin signaling, suppresses glycolysis, compromises T-cell cytotoxicity, and induces systemic immune senescence. Therapeutic targeting of the CLDN18.2-β-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.
Disclosure
J. Yan, None.
Cited in
Control: 149 · Presentation Id: 1351 · Meeting 21436