University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, United States.
Front Immunol. 2022 Oct 18;13:992630. doi: 10.3389/fimmu.2022.992630. eCollection 2022.
Differential responses to immune checkpoint inhibitors (ICI) may be attributed to tumor-intrinsic factors or environmental cues; however, these mechanisms cannot fully explain the variable ICI responses in different individuals. Here, we investigate the potential contribution of immunological heterogeneity with a focus on differences in T-cell receptor (TCR) repertoire to ICI responses, which has not been defined previously. To reveal additional factors underlying heterogeneous responses to ICI, we employed a squamous cell carcinoma (SCC) mouse model in which tumor-bearing recipients unambiguously diverged into responders (R) or non-responders (NR) upon anti-PD-L1 treatment. Treatment efficacy absolutely required CD8 T-cells and correlated positively with effector functions of CD8 tumor-infiltrating lymphocytes (TILs). We showed that TCR repertoires exhibited a similar magnitude of clonal expansion in R . NR CD8 TILs. However, the top expanded TCR clonotypes appeared to be mutually exclusive between R and NR CD8 TILs, which also occurred in a recipient-specific manner, demonstrating preferential expansion of distinct TCR clonotypes against the same SCC tumor. Unexpectedly, R . NR CD8 TILs reached all activation clusters and did not exhibit substantial global differences in transcriptomes. By linking single-cell transcriptomic data with unique TCR clonotypes, CD8 TILs harboring top TCR clonotypes were found to occupy distinct activation clusters and upregulate genes favoring anti-tumor immunity to different extents in R . NR. We conclude that stochastic differences in CD8 TIL TCR repertoire and distinct activation states of top TCR clonotypes may contribute to differential anti-PD-L1 responses. Our study suggests that host-intrinsic immunological heterogeneity may offer a new explanation for differential ICI responses in different individuals, which could impact on strategies for personalized cancer immunotherapy.
免疫检查点抑制剂（ICI）的反应差异可能归因于肿瘤内在因素或环境线索；然而，这些机制不能完全解释不同个体中 ICI 反应的可变性。在这里，我们研究了免疫异质性的潜在贡献，重点关注 T 细胞受体（TCR）库的差异对 ICI 反应的影响，这在以前尚未确定。为了揭示 ICI 反应异质性的其他潜在因素，我们使用了鳞状细胞癌（SCC）小鼠模型，在该模型中，荷瘤受体在接受抗 PD-L1 治疗后明确分为应答者（R）或无应答者（NR）。治疗效果绝对需要 CD8 T 细胞，并且与 CD8 肿瘤浸润淋巴细胞（TIL）的效应功能呈正相关。我们表明，R 和 NR CD8 TIL 中的 TCR 库均表现出相似程度的克隆扩增。然而，在 R 和 NR CD8 TIL 之间，顶级扩增的 TCR 克隆型似乎是相互排斥的，这也以受体特异性的方式发生，表明针对相同 SCC 肿瘤的不同 TCR 克隆型存在优先扩增。出乎意料的是，R 和 NR CD8 TIL 达到了所有激活簇，并且在转录组中没有表现出实质性的全局差异。通过将单细胞转录组数据与独特的 TCR 克隆型联系起来，发现携带顶级 TCR 克隆型的 CD8 TIL 占据不同的激活簇，并在 R 和 NR 中不同程度地上调有利于抗肿瘤免疫的基因。我们得出结论，CD8 TIL TCR 库中的随机差异和顶级 TCR 克隆型的不同激活状态可能导致抗 PD-L1 反应的差异。我们的研究表明，宿主内在的免疫异质性可能为不同个体中 ICI 反应的差异提供新的解释，这可能会影响个性化癌症免疫治疗的策略。
