Rojas-Diaz Jose Manuel, Solorzano-Ibarra Fabiola, Garcia-Barrientos Nadia Tatiana, Klimov-Kravtchenko Ksenia, Cruz-Ramos Jose Alfonso, Guitron-Aviña Marcela Sofia, Urciaga-Gutierrez Pedro Ivan, Ortiz-Lazareno Pablo Cesar, Tellez-Bañuelos Martha Cecilia, Bueno-Topete Miriam Ruth, Haramati Jesse, Del Toro-Arreola Susana
Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico.
Coordinación de Investigación, Subdirección de Desarrollo Institucional, Instituto Jalisciense de Cancerología, Guadalajara, Jalisco, Mexico.
Immunology. 2025 Aug;175(4):482-500. doi: 10.1111/imm.13945. Epub 2025 May 19.
T cells are pivotal in combating cancer; however, they can become exhausted during tumour progression, losing their cytotoxic capacity and upregulating inhibitory receptors including PD-1 and TIGIT. While checkpoint blockade has emerged as a potent treatment option for numerous cancers, patient selection, long-term efficacy, and adverse effects still remain an issue. For these reasons, it is important to investigate other pathways that might lead to selective reactivation of the immune system. Co-stimulatory TNFRSF receptors, including 4-1BB and OX-40, have emerged as promising targets for reactivating exhausted T cells. However, their expression on exhausted peripheral and tumour-infiltrating lymphocytes (TILs) is not well characterised, particularly in cervical cancer (CC), which remains the leading cause of gynaecological cancer mortality in low- and middle-income countries. To investigate the expression of these receptors, PBMCs were collected from CC patients and healthy donors, along with TILs from tumour biopsies, and analysed using multiparametric flow cytometry. Our findings revealed an increased population of phenotypically exhausted (PD-1TIGIT) CD4 and CD8 T cells in TILs, and, to a lesser extent, in peripheral blood and from CC patients. These exhausted T cell subsets exhibited selective overexpression of 4-1BB and OX-40 compared to phenotypically non-exhausted cells (PD-1TIGIT). In TILs, 4-1BB was overexpressed 12.7-fold in CD8 cells with the exhausted phenotype, OX-40 was overexpressed 3.3-fold; in CD4 cells with the exhausted phenotype, the overexpression was 7.8× and 3.8× for 4-1BB and OX-40, respectively. CD8 and CD4 T cells that were PD-1 + TIGIT+ 4-1BB+ were 7.3× and 16× more likely to be found in the tumour versus peripheral blood. Additionally, subpopulations of PD-1 T cells were significantly elevated in the tumour-infiltrating T cells and TIGIT expression was positively associated with PD-1 levels in peripheral patient CD8 and CD4 T cells, potentially indicating an advanced state of exhaustion. These findings suggest that TNFRSF members, especially 4-1BB, may serve as potential immunotherapeutic targets for reinvigorating exhausted T cells in CC.
T细胞在对抗癌症中起着关键作用；然而，它们在肿瘤进展过程中可能会耗竭，失去细胞毒性能力，并上调包括PD-1和TIGIT在内的抑制性受体。虽然检查点阻断已成为许多癌症的有效治疗选择，但患者选择、长期疗效和不良反应仍然是一个问题。出于这些原因，研究其他可能导致免疫系统选择性重新激活的途径很重要。共刺激TNFRSF受体，包括4-1BB和OX-40，已成为重新激活耗竭T细胞的有希望的靶点。然而，它们在耗竭的外周血和肿瘤浸润淋巴细胞（TILs）上的表达尚未得到很好的表征，特别是在宫颈癌（CC）中，宫颈癌仍然是低收入和中等收入国家妇科癌症死亡的主要原因。为了研究这些受体的表达，从CC患者和健康供体中收集外周血单核细胞（PBMC），以及肿瘤活检组织中的TILs，并使用多参数流式细胞术进行分析。我们的研究结果显示，TILs中表型耗竭（PD-1+TIGIT+）的CD4和CD8 T细胞数量增加，在外周血和CC患者中也有一定程度的增加。与表型未耗竭的细胞（PD-1-TIGIT-）相比，这些耗竭的T细胞亚群表现出4-1BB和OX-40的选择性过表达。在TILs中，具有耗竭表型的CD8细胞中4-1BB过表达12.7倍，OX-40过表达3.3倍；在具有耗竭表型的CD4细胞中，4-1BB和OX-40的过表达分别为7.8倍和3.8倍。与外周血相比，肿瘤中PD-1+TIGIT+4-1BB+的CD8和CD4 T细胞出现可能性分别高7.3倍和16倍。此外，肿瘤浸润T细胞中PD-1+T细胞亚群显著升高，并且TIGIT表达与患者外周血CD8和CD4 T细胞中的PD-1水平呈正相关，这可能表明耗竭程度更高。这些发现表明，TNFRSF成员，特别是4-1BB，可能作为恢复CC中耗竭T细胞活力的潜在免疫治疗靶点。
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