Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia.
Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia.
Clin Cancer Res. 2024 May 1;30(9):1833-1845. doi: 10.1158/1078-0432.CCR-23-1316.
Combination of chemotherapy with programmed cell death 1 (PD-1) blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how chemotherapy affects the response of exhausted CD8 T cells to PD-1 blockade.
We used the well-established mouse model of T-cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to assess the effect of chemotherapy (cisplatin+pemetrexed) on T-cell response to PD-1 blockade, in the absence of the impact of chemotherapy on antigen release and presentation observed in tumor models.
When concomitantly administered with PD-1 blockade, chemotherapy affected the differentiation path of LCMV-specific CD8 T cells from stem-like to transitory effector cells, thereby reducing their expansion and production of IFNγ. After combination treatment, these restrained effector responses resulted in impaired viral control, compared with PD-1 blockade alone. The sequential combination strategy, where PD-1 blockade followed chemotherapy, proved to be superior to the concomitant combination, preserving the proliferative response of exhausted CD8 T cells to PD-1 blockade. Our findings suggest that the stem-like CD8 T cells themselves are relatively unaffected by chemotherapy partly because they are quiescent and maintained by slow self-renewal at the steady state. However, upon the proliferative burst mediated by PD-1 blockade, the accelerated differentiation and self-renewal of stem-like cells may be curbed by concomitant chemotherapy, ultimately resulting in impaired overall CD8 T-cell effector functions.
In a translational context, we provide a proof-of-concept to consider optimizing the timing of chemo-immunotherapy strategies for improved CD8 T-cell functions. See related commentary by Vignali and Luke, p. 1705.
化疗联合程序性细胞死亡 1（PD-1）阻断是肺癌的一线治疗方法。然而，目前尚不清楚化疗是否以及如何影响耗竭 CD8 T 细胞对 PD-1 阻断的反应。
我们使用慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染的成熟小鼠模型来评估化疗（顺铂+培美曲塞）对 PD-1 阻断时 T 细胞反应的影响，同时避免了在肿瘤模型中观察到的化疗对抗原释放和呈递的影响。
当与 PD-1 阻断同时给药时，化疗影响了 LCMV 特异性 CD8 T 细胞从干细胞样到短暂效应细胞的分化途径，从而减少了它们的扩增和 IFNγ的产生。与 PD-1 阻断单独治疗相比，联合治疗后，这些受限的效应反应导致病毒控制受损。与同时联合治疗相比，PD-1 阻断后序贯联合治疗策略更具优势，保留了耗竭 CD8 T 细胞对 PD-1 阻断的增殖反应。我们的研究结果表明，干细胞样 CD8 T 细胞本身受化疗的影响相对较小，部分原因是它们在静息状态下通过缓慢的自我更新而处于静止状态。然而，在 PD-1 阻断介导的增殖爆发后，干细胞样细胞的加速分化和自我更新可能会被同时的化疗所抑制，最终导致整体 CD8 T 细胞效应功能受损。
在转化背景下，我们提供了一个概念验证，以考虑优化化疗免疫治疗策略的时间，以改善 CD8 T 细胞功能。请参阅 Vignali 和 Luke 的相关评论，第 1705 页。
