Paolini Léa, Tran Thi, Corgnac Stéphanie, Villemin Jean-Philippe, Wislez Marie, Arrondeau Jennifer, Johannes Ludger, Ulmer Jonathan, Vieillard Louis-Victorien, Pineau Joséphine, Gey Alain, Quiniou Valentin, Barennes Pierre, Pham Hang Phuong, Gruel Nadège, Hasan Milena, Libri Valentina, Mella Sebastien, De Percin Sixtine, Boudou-Rouquette Pascaline, Caidi Aziza, Cremer Isabelle, Blons Hélène, Leroy Karen, Laurent-Puig Pierre, De Saint Basile Hortense, Gibault Laure, Ravel Patrice, Mami-Chouaib Fathia, Goldwasser François, Fabre Elizabeth, Damotte Diane, Tartour Eric
Université Paris Cité, INSERM, PARCC, Paris, France, Paris, France.
INSERM UMR1186, Gustave Roussy, Fac.de Medecine-Univ Paris-Sud, Université Paris-Saclay, Villejuif, France, INSERM, Villejuif, France.
J Immunother Cancer. 2024 Dec 3;12(12):e009440. doi: 10.1136/jitc-2024-009440.
A high density of resident memory T cells (T) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. In most clinical studies, T are defined by the CD103 marker. However, it is clearly established that not all T express CD103, but can be defined by other markers (CD49a, CD69, etc). The frequency of these subpopulations of T expressing or not CD103 varies according to the location of the cancer. Little is known about their functionality and their predictive impact on response to immunotherapy. In preclinical models, only some subpopulations of T are associated with cancer vaccine efficacy.
Multiparametric cytometry analyses were used to demonstrate the presence of T subpopulations in the lung in mice after vaccination and in fresh ex vivo human non-small cell lung cancer (NSCLC). An analysis of the T-cell repertoire of these T was conducted to search for their relationships. Multiplex immunofluorescence techniques were used to quantify intratumor infiltration of T subpopulations in two cohorts of patients with NSCLC. The impact on the clinical outcome of the T tumor infiltration was also investigated.
We identified two main T subpopulations in tumor-infiltrating lymphocytes derived from patients with NSCLC: one co-expressing CD103 and CD49a (double positive (DP)), and the other expressing only CD49a (simple positive (SP)); both exhibiting additional T surface markers like CD69. Despite higher expression of inhibitory receptors, DP T exhibited greater functionality compared with SP T. Analysis of T-cell receptor (TCR) repertoire and expression of the stemness marker TCF1 revealed shared TCRs between populations, with the SP subset appearing more progenitor-like phenotype. In the training cohort, PD-L1 (Programmed Death-Ligand 1) and TCF1CD8T cells predict response to anti-PD-1. In patient with NSCLC validation cohorts, only DP T predicted PD-1 blockade response. Multivariate analysis, including various biomarkers associated with responses to anti-PD-(L)1, such as total CD8, TCF1CD8T cells, and PD-L1, showed that only intratumoral infiltration by DP T remained significant.
This study highlights the non-equivalence of T subpopulations. The population of T co-expressing CD103 and CD49a appears to be the most functional and has the most significant capacity for predicting response to immunotherapy in multivariate analysis in patients with NSCLC.
肿瘤中驻留记忆T细胞（T细胞）的高密度与免疫治疗患者的临床结局改善相关。在大多数临床研究中，T细胞由CD103标志物定义。然而，已明确并非所有T细胞都表达CD103，而是可以由其他标志物（CD49a、CD69等）定义。这些表达或不表达CD103的T细胞亚群的频率因癌症位置而异。关于它们的功能及其对免疫治疗反应的预测影响知之甚少。在临床前模型中，只有一些T细胞亚群与癌症疫苗疗效相关。
采用多参数细胞术分析来证明接种疫苗后小鼠肺部以及新鲜离体人非小细胞肺癌（NSCLC）中T细胞亚群的存在。对这些T细胞的T细胞库进行分析以寻找它们之间的关系。使用多重免疫荧光技术对两组NSCLC患者肿瘤内T细胞亚群的浸润情况进行定量。还研究了T细胞肿瘤浸润对临床结局的影响。
我们在源自NSCLC患者的肿瘤浸润淋巴细胞中鉴定出两个主要的T细胞亚群：一个共表达CD103和CD49a（双阳性（DP）），另一个仅表达CD49a（单阳性（SP））；两者均表现出如CD69等其他T细胞表面标志物。尽管抑制性受体表达较高，但与SP T细胞相比，DP T细胞表现出更大的功能。对T细胞受体（TCR）库和干性标志物TCF1表达的分析揭示了不同群体之间共享的TCR，SP亚群表现出更类似祖细胞的表型。在训练队列中，程序性死亡配体1（PD-L1）和TCF1 CD8 T细胞可预测对抗PD-1的反应。在NSCLC验证队列患者中，只有DP T细胞可预测PD-1阻断反应。多变量分析包括与抗PD-(L)1反应相关的各种生物标志物，如总CD8、TCF1 CD8 T细胞和PD-L1，结果显示只有DP T细胞的肿瘤内浸润仍然具有显著性。
本研究强调了T细胞亚群的不等效性。共表达CD103和CD49a的T细胞群体似乎功能最强，并且在NSCLC患者的多变量分析中具有预测免疫治疗反应的最显著能力。
