Yang Zike, Zhu Ying, Wang Qian, Lin Qing, Liu Yahui
Department of Oncology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Department of Obstetrics and Gynecology, The Third Affiliated Hospital/The Third Clinical Medicine School of Southern Medical University, Guangzhou, China.
Front Immunol. 2025 May 2;16:1563894. doi: 10.3389/fimmu.2025.1563894. eCollection 2025.
Lymphopenia induced by radiotherapy or chemotherapy can promote homeostatic proliferation of residual or adoptive lymphocytes, potentially enhancing antitumor immunity. However, this immunity diminishes rapidly with tumor progression, and the underlying mechanisms remain unclear. This study investigates the role of PD-1 signaling in homeostatic proliferation-induced antitumor immunity in malignant melanoma.
We evaluated T-cell dynamics in lymphopenic mice, analyzing PD-1 expression, IFN-γ production by CD8 T cells, and T-cell cytotoxicity during homeostatic proliferation. The PD-1/PD-L1 axis was blocked using anti-PD-1 antibodies to assess its impact on T-cell function, dendritic cell (DC) activation, and memory T-cell differentiation.
Although T cells proliferated continuously in lymphopenic mice, IFN-γ+ CD8 T cells declined over time. PD-1 expression on T cells increased progressively and correlated negatively with effector T-cell cytotoxicity. PD-1 blockade enhanced the recognition of tumor-associated antigens (TAAs) by homeostatically proliferating (HP) T cells, activated DCs, and increased IFN-γ+ CD8+ T-cell numbers. Additionally, it boosted T-cell cytotoxicity and promoted the conversion of tumor-specific effector T cells into central memory T cells.
These findings indicate that the PD-1/PD-L1 axis plays a critical role in immune tolerance during homeostatic proliferation. Anti-PD-1 therapy may enhance antitumor immunity during lymphopenia recovery after chemotherapy or radiotherapy, offering a potential strategy to sustain T-cell-mediated tumor control.
放疗或化疗诱导的淋巴细胞减少可促进残余或过继性淋巴细胞的稳态增殖，潜在地增强抗肿瘤免疫力。然而，随着肿瘤进展，这种免疫力会迅速减弱，其潜在机制仍不清楚。本研究调查了PD-1信号在恶性黑色素瘤稳态增殖诱导的抗肿瘤免疫中的作用。
我们评估了淋巴细胞减少小鼠中的T细胞动态，分析了稳态增殖期间的PD-1表达、CD8 T细胞产生的IFN-γ以及T细胞的细胞毒性。使用抗PD-1抗体阻断PD-1/PD-L1轴，以评估其对T细胞功能、树突状细胞（DC）激活和记忆T细胞分化的影响。
尽管T细胞在淋巴细胞减少的小鼠中持续增殖，但IFN-γ+ CD8 T细胞随时间下降。T细胞上的PD-1表达逐渐增加，并与效应T细胞的细胞毒性呈负相关。PD-1阻断增强了稳态增殖（HP）T细胞对肿瘤相关抗原（TAA）的识别，激活了DC，并增加了IFN-γ+ CD8+ T细胞数量。此外，它增强了T细胞的细胞毒性，并促进了肿瘤特异性效应T细胞向中央记忆T细胞的转化。
这些发现表明，PD-1/PD-L1轴在稳态增殖期间的免疫耐受中起关键作用。抗PD-1治疗可能在化疗或放疗后淋巴细胞减少恢复期间增强抗肿瘤免疫力，提供一种维持T细胞介导的肿瘤控制的潜在策略。
