PO.IM02.04 · 免疫学
Th7R细胞：驱动Tpex介导的肿瘤微环境内抗肿瘤免疫的CD4⁺ T细胞伙伴
Th7R cells: CD4⁺ T-cell partners that drive Tpex-mediated antitumor immunity in the tumor microenvironment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：前体耗竭型CD8⁺ T细胞（Tpex）是一类可自我更新、具有干细胞样特性的CD8⁺ T细胞，能够产生终末耗竭型（Tex）细胞并维持长期抗肿瘤免疫。在肿瘤微环境（TME）内，Tpex定位于三级淋巴样结构（TLS）和高内皮微静脉（HEV），并在PD-1阻断后触发CD8⁺ T细胞的爆发性扩增。然而，支持Tpex生成与维持的CD4⁺ T细胞亚群仍不明确。我们此前在肺癌中鉴定出Th7R细胞，这是一种Th1样CD4⁺ T细胞亚群（CCR4⁻CCR6⁺，表达IL7R和TCF7），与免疫检查点抑制剂（ICI）的应答相关。Th7R与Tpex共享干细胞样特征，提示两者可能存在协作关系。
目的：验证Th7R细胞是否作为CD4⁺伙伴维持Tpex及长期抗肿瘤免疫，并评估Th7R过继转移的抗肿瘤疗效。
方法：我们分析了55例接受切除术的早期肺癌患者以及20例接受新辅助抗PD-1治疗的II-III期患者。通过质谱流式细胞术和成像质谱流式细胞术对外周血、肿瘤浸润淋巴细胞（TIL）及淋巴结T细胞进行表型分析，以评估Th7R与Tpex在空间和数量上的关系。在小鼠MCA205模型中，将从肿瘤引流淋巴结分选并扩增的CCR4⁻CCR6⁺ Th7R细胞进行过继转移，以评估抗肿瘤效果及其对TIL的影响。
结果：术前Th7R频率高的患者显示出更好的无病生存期。Th7R（而非其他CD4⁺亚群）在肿瘤切除后减少，提示其扩增由肿瘤抗原驱动。在新辅助治疗病例中，完全或主要病理缓解者的Th7R细胞比例更高。Th7R与Tpex在血液和淋巴结中均呈正相关。成像质谱流式细胞术显示Th7R细胞定位于TLS内Tpex附近。在小鼠中，Th7R转移诱导肿瘤消退，并特异性扩增Tpex和Tex两个亚群。
结论：Th7R细胞在数量和空间上与Tpex相关联，对维持长期抗肿瘤免疫至关重要。它们可能促进Tpex的不对称分裂，维持其自我更新和效应细胞供应。Th7R过继转移，无论单独使用还是与ICI联用，都代表了一种增强持久抗肿瘤免疫的有前景的方法。
查看英文原文 English abstract
Background: Precursor-exhausted CD8⁺ T cells (Tpex) are self-renewing, stem-like CD8⁺ T cells that give rise to terminally exhausted (Tex) cells and maintain long-term antitumor immunity. Within the tumor microenvironment (TME), Tpex localize to tertiary lymphoid structures (TLSs) and high endothelial venules (HEVs) and trigger the CD8⁺ T-cell burst after PD-1 blockade. However, the CD4⁺ T-cell subsets that support Tpex generation and maintenance remain unclear. We previously identified Th7R cells, a Th1-like CD4⁺ T-cell subset (CCR4⁻CCR6⁺, expressing IL7R and TCF7) in lung cancer, associated with immune checkpoint inhibitor (ICI) responsiveness. Th7R and Tpex share stem-like signatures, suggesting a potential partnership.
Objective: To test whether Th7R cells function as CD4⁺ partners sustaining Tpex and long-term antitumor immunity, and to evaluate the antitumor efficacy of Th7R adoptive transfer.
Methods: We analyzed 55 early-stage lung cancer patients undergoing resection and 20 stage II-III patients treated with neoadjuvant anti-PD-1 therapy. Peripheral blood, tumor-infiltrating lymphocytes (TILs), and lymph node T cells were profiled by mass and imaging mass cytometry to assess the spatial and numerical relationship between Th7R and Tpex. In a mouse MCA205 model, CCR4⁻CCR6⁺ Th7R cells sorted and expanded from tumor-draining lymph nodes were adoptively transferred to evaluate antitumor effects and their impact on TILs.
Results: Patients with high preoperative Th7R frequency showed better disease-free survival. Th7R-but not other CD4⁺ subsets-decreased after tumor resection, indicating tumor antigen-driven expansion. In neoadjuvant cases, complete or major pathological responders had higher proportions of Th7R cells. Th7R and Tpex showed a positive correlation in both blood and lymph nodes. Imaging mass cytometry showed Th7R cells located near Tpex within TLSs. In mice, Th7R transfer induced tumor regression and specifically expanded both Tpex and Tex subsets.
Conclusion: Th7R cells are numerically and spatially associated with Tpex and crucial for sustaining long-term antitumor immunity. They may promote asymmetric Tpex division, maintaining renewal and effector supply. Th7R adoptive transfer, alone or with ICIs, represents a promising approach to enhance durable antitumor immunity.
利益披露 Disclosure
S. Takei, None..
O. Yamaguchi, None..
S. Yamasaki, None..
A. Mouri, None..
A. Shiono, None..
Y. Miura, None..
K. Hashimoto, None..
H. Imai, None..
K. Kaira, None..
I. Yoshinobu, None..
H. Nitanda, None..
T. Hishida, None..
K. Horimoto, None.
H. Kagamu,
Saitama Medical University Patent.
Boehringer-Ingelheim ).