Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Int J Radiat Oncol Biol Phys. 2022 Jun 1;113(2):415-425. doi: 10.1016/j.ijrobp.2022.02.003. Epub 2022 Feb 10.
Chemoradiotherapy (CRT) followed by consolidation immune checkpoint inhibitors significantly improves survival in unresectable locally advanced non-small cell lung cancer. However, the optimal sequence for CRT and immune checkpoint inhibitors has not yet been established. We investigated the dynamics of peripheral blood immune cells during CRT to determine the best sequence for treatment.
Peripheral blood samples were prospectively collected pretreatment, weekly during CRT for 6 weeks, and 1 month posttreatment in 24 patients with locally advanced non-small cell lung cancer who received definitive CRT. Immune cell analysis was performed by flow cytometry. Ex vivo PD-1 blockade assays were performed by IFN-γ intracellular cytokine staining.
Lymphopenia was prominently observed during CRT and mostly recovered 1 month post-CRT. Robust proliferation of CD8 T cells was induced, peaking in the last week during CRT and decreasing post-CRT. The robust proliferation of CD8 T cells led to an increase in the frequency of CD28CD57 replicative senescent and terminally differentiated cells post-CRT. Tumor-reactive CD8 T cells increased during CRT and peaked in the last week. One month post-CRT, the frequency of tumor-reactive CD8 T cells decreased and TOXTCF1 terminally exhausted CD8 T cells significantly increased. Anti-PD-1-induced functional restoration of PD-1CD8 T cells was maximized in the last week of CRT and significantly decreased post-CRT.
The findings suggest that earlier administration of PD-1 blockade may be associated with superior efficacy compared with delayed administration after completion of CRT. These findings provide an immunologic rationale for optimal timing of combining immune checkpoint inhibitors with CRT in clinical trials.
放化疗（CRT）后巩固免疫检查点抑制剂治疗显著改善了不可切除局部晚期非小细胞肺癌患者的生存。然而，CRT 和免疫检查点抑制剂的最佳顺序尚未确定。我们研究了 CRT 期间外周血免疫细胞的动态变化，以确定治疗的最佳顺序。
前瞻性收集 24 例局部晚期非小细胞肺癌患者在接受根治性 CRT 治疗前、每周 CRT 期间 6 周、治疗后 1 个月的外周血样本。通过流式细胞术进行免疫细胞分析。通过 IFN-γ 细胞内细胞因子染色进行体外 PD-1 阻断试验。
CRT 期间明显观察到淋巴细胞减少，且在 CRT 后 1 个月大部分恢复。CD8 T 细胞强烈增殖，在 CRT 的最后一周达到高峰，并在 CRT 后减少。CD8 T 细胞的强烈增殖导致 CRT 后 CD28CD57 复制衰老和终末分化细胞的频率增加。CRT 期间肿瘤反应性 CD8 T 细胞增加，并在最后一周达到高峰。CRT 后 1 个月，肿瘤反应性 CD8 T 细胞的频率下降，TOXTCF1 终末耗尽的 CD8 T 细胞显著增加。抗 PD-1 诱导 PD-1CD8 T 细胞的功能恢复在 CRT 的最后一周达到最大值，并在 CRT 后显著降低。
这些发现表明，与 CRT 完成后延迟给药相比，早期给予 PD-1 阻断可能与更好的疗效相关。这些发现为临床试验中免疫检查点抑制剂与 CRT 联合应用的最佳时机提供了免疫学依据。
