LBPO.IM03 · 免疫学 · Late-Breaking
用LAG3导向的白细胞介素-2靶向肿瘤特异性T细胞可防止T细胞耗竭并重振抗肿瘤免疫
Targeting tumor-specific T cells with LAG3-directed interleukin-2 prevents T cell exhaustion and reinvigorates antitumor immunity
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摘要 Abstract
中文摘要
LAG3是一种关键的抑制性受体，在肿瘤微环境（TME）内的耗竭T细胞上高度富集，在其中作为T细胞耗竭的关键驱动因素发挥作用——耗竭是强健抗肿瘤免疫的典型障碍。在结肠癌模型中，我们发现LAG3⁺CD8⁺肿瘤浸润淋巴细胞（TIL）构成了主要的肿瘤特异性T细胞，但表现出IL2信号缺陷。为了探讨外源性IL2补充能否解除其功能障碍，我们工程化构建了LAG3-LaIL2（低亲和力IL2）融合蛋白，将IL2选择性递送至LAG3⁺CD8⁺TIL。LAG3-LaIL2扩增了预耗竭的肿瘤特异性CD8⁺ T细胞，将其耗竭轨迹重编程为中间效应状态，并防止了终末耗竭，从而在小鼠中带来肿瘤消退和生存期延长。从机制上讲，LAG3-LaIL2通过上调高亲和力IL2受体亚基CD122恢复了IL2R-JAK3-STAT5信号传导，从而使TIL功能重焕活力。此外，LAG3-LaIL2在引流淋巴结中扩增了肿瘤特异性效应和记忆T细胞，实现了针对远端肿瘤的系统性抗肿瘤免疫并防止肿瘤复发。总之，我们的发现验证了LAG3-LaIL2作为一种精准免疫治疗药物，可特异性靶向耗竭的TIL，同时通过限制IL2对非靶细胞的暴露来增强治疗疗效和安全性。该策略提供了一种可转化的方法来克服实体瘤中的T细胞耗竭，为改善癌症患者临床结局提供了一条有前景的途径。
查看英文原文 English abstract
LAG3 is a critical inhibitory receptor that is highly enriched on exhausted T cells within the tumor microenvironment (TME), where it functions as a key driver of T cell exhaustion-an archetypal barrier to robust antitumor immunity. In a colon cancer model, we identified that LAG3 + CD8 + tumor-infiltrating lymphocytes (TILs) constitute the predominant tumor-specific T cells but exhibit defective IL2 signaling. To address whether exogenous IL2 replenishment unpins their dysfunction, we engineered LAG3-LaIL2 (low-affinity IL2), a fusion protein delivering IL2 selectively to LAG3 + CD8 + TILs. LAG3-LaIL2 expanded pre-exhausted tumor-specific CD8 + T cells, reprogrammed their exhaustion trajectory toward an intermediate effector state, and prevented terminal exhaustion, leading to tumor regression and prolonged survival in mice. Mechanistically, LAG3-LaIL2 restored IL2R-JAK3-STAT5 signaling by upregulating the high-affinity IL2 receptor subunit CD122, thereby rejuvenating TIL functionality. Furthermore, LAG3-LaIL2 amplified tumor-specific effector and memory T cells in draining lymph nodes, enabling systemic antitumor immunity against distal tumors and preventing tumor recurrence. Collectively, our findings validate LAG3-LaIL2 as a precision immunotherapeutic agent that specifically targets exhausted TILs, concomitantly enhancing therapeutic efficacy and safety by restricting IL2 exposure to non-target cells. This strategy provides a translatable approach to overcoming T cell exhaustion in solid tumors, offering a promising avenue to improve clinical outcomes for cancer patients.
利益披露 Disclosure
Z. Ren, None..
X. Yu, None..
Y. Fu, None.