Karjalainen Henna, Härkönen Jouni, Sirniö Päivi, Elomaa Hanna, Äijälä Ville K, Kastinen Meeri, Tapiainen Vilja V, Väyrynen Sara A, Ahtiainen Maarit, Helminen Olli, Wirta Erkki-Ville, Rintala Jukka, Meriläinen Sanna, Saarnio Juha, Rautio Tero, Seppälä Toni T, Böhm Jan, Mecklin Jukka-Pekka, Tuomisto Anne, Mäkinen Markus J, Väyrynen Juha P
Translational Medicine Research Unit, University of Oulu, Oulu University Hospital, Oulu, Finland.
Department of Pathology, Hospital Nova of Central Finland, Well Being Services County of Central Finland, Jyväskylä, Finland.
Oncoimmunology. 2025 Dec;14(1):2532231. doi: 10.1080/2162402X.2025.2532231. Epub 2025 Jul 28.
Gamma-delta T cells are a subset of T cells that have features of both innate and adaptive immunity. Their role in cancer remains controversial, since both anti- and protumor functions have been reported. We aimed to shed light on the distinct characteristics of γδ T cells in colorectal cancer (CRC). In two independent cohorts, including 1 687 CRC patients, we identified γδ and αβ T cells with multiplex immunohistochemistry to evaluate their prognostic significance. To further analyze the characteristics of γδ T cells, we utilized single-cell RNA sequencing data of 62 CRC patients. High γδ T cell densities were associated with prolonged survival in both cohorts, and this association was independent of other tumor and patient characteristics in Cohort 1, where the multivariable HR for high (vs. low) γδ T cell density was 0.65 (95% CI 0.47-0.90), while the corresponding HR in Cohort 2 was 0.82 (0.50-1.33). αβ T cells demonstrated a stronger association with longer survival that was independent of other prognostic factors in both cohorts. γδ T cells were enriched in mismatch repair (MMR) deficient and mutated tumors. Single-cell RNA sequencing analysis revealed that γδ T cells were abundant in tumors with weak antigen presentation signaling in tumor cells. Immunohistochemically, high γδ T cell densities were associated with beta-2 microglobulin loss independent of MMR status. These findings indicate that γδ T cells are associated with prolonged survival in CRC and are concentrated in tumors with impaired antigen presentation and MMR deficiency.
γδ T细胞是T细胞的一个亚群，具有先天免疫和适应性免疫的特征。它们在癌症中的作用仍存在争议，因为既有抗肿瘤功能的报道，也有促肿瘤功能的报道。我们旨在阐明γδ T细胞在结直肠癌（CRC）中的独特特征。在两个独立队列中，包括1687例CRC患者，我们采用多重免疫组化鉴定γδ和αβ T细胞，以评估它们的预后意义。为了进一步分析γδ T细胞的特征，我们利用了62例CRC患者的单细胞RNA测序数据。在两个队列中，高γδ T细胞密度均与生存期延长相关，在队列1中，这种关联独立于其他肿瘤和患者特征，其中高（vs.低）γδ T细胞密度的多变量HR为0.65（95%CI 为0.47-0.90），而队列2中的相应HR为0.82（0.50-1.33）。αβ T细胞在两个队列中均显示出与更长生存期的更强关联，且独立于其他预后因素。γδ T细胞在错配修复（MMR）缺陷和突变肿瘤中富集。单细胞RNA测序分析显示，γδ T细胞在肿瘤细胞中抗原呈递信号较弱的肿瘤中丰富。免疫组化显示，高γδ T细胞密度与β2微球蛋白缺失相关，且独立于MMR状态。这些发现表明，γδ T细胞与CRC患者生存期延长相关，并集中在抗原呈递受损和MMR缺陷的肿瘤中。
