Institut Pasteur, Université de Paris Cité, INSERM U1223 , Paris, France.
Human Disease Models Core Facility, Institut Pasteur, Paris, France.
J Exp Med. 2024 Apr 1;221(4). doi: 10.1084/jem.20232104. Epub 2024 Feb 28.
Anti-PD-1 therapy targets intratumoral CD8+ T cells to promote clinical responses in cancer patients. Recent evidence suggests an additional activity in the periphery, but the underlying mechanism is unclear. Here, we show that anti-PD-1 mAb enhances CD8+ T cell responses in tumor-draining lymph nodes by stimulating cytokine production in follicular helper T cells (Tfh). In two different models, anti-PD-1 mAb increased the activation and proliferation of tumor-specific T cells in lymph nodes. Surprisingly, anti-PD-1 mAb did not primarily target CD8+ T cells but instead stimulated IL-4 production by Tfh cells, the major population bound by anti-PD-1 mAb. Blocking IL-4 or inhibiting the Tfh master transcription factor BCL6 abrogated anti-PD-1 mAb activity in lymph nodes while injection of IL-4 complexes was sufficient to recapitulate anti-PD-1 mAb activity. A similar mechanism was observed in a vaccine model. Finally, nivolumab also boosted human Tfh cells in humanized mice. We propose that Tfh cells and IL-4 play a key role in the peripheral activity of anti-PD-1 mAb.
抗 PD-1 治疗针对肿瘤内 CD8+T 细胞，以促进癌症患者的临床反应。最近的证据表明在外周具有额外的活性，但潜在机制尚不清楚。在这里，我们表明抗 PD-1 mAb 通过刺激滤泡辅助 T 细胞（Tfh）中的细胞因子产生，增强肿瘤引流淋巴结中 CD8+T 细胞的反应。在两种不同的模型中，抗 PD-1 mAb 增加了淋巴结中肿瘤特异性 T 细胞的激活和增殖。令人惊讶的是，抗 PD-1 mAb 并非主要针对 CD8+T 细胞，而是刺激 Tfh 细胞产生 IL-4，Tfh 细胞是被抗 PD-1 mAb 结合的主要群体。阻断 IL-4 或抑制 Tfh 主转录因子 BCL6 可消除淋巴结中抗 PD-1 mAb 的活性，而注射 IL-4 复合物足以重现抗 PD-1 mAb 的活性。在疫苗模型中也观察到类似的机制。最后，纳武单抗也在人源化小鼠中增强了人类 Tfh 细胞。我们提出 Tfh 细胞和 IL-4 在抗 PD-1 mAb 的外周活性中发挥关键作用。
