The significance of CD8+ tumor-infiltrating lymphocytes exhaustion heterogeneity and its underlying mechanism in diffuse large B-cell lymphoma

• Published in: International immunopharmacology 2024-08, Vol.137, p.112447, Article 112447
• Main Authors: Zhu, Qiqi, Yang, Yiming, Zeng, Yi, Chen, Kexin, Zhang, Qiaoyu, Wang, Li, Huang, Yifan, Jian, Shunhai
• Format: Article
• Language: English
• Subjects: A2AR; CD39; CD8+ tumor-infiltrating lymphocytes; Diffuse large B-cell lymphoma; Immunotherapy; Progenitor and terminally exhaustion; Prognosis; Single-cell RNA sequencing
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112447

[Display omitted] •Terminally exhausted CD8+ tumor-infiltrating lymphocytes, which may be induced by CD39/A2AR-related signaling pathway, are correlated with progressive diffuse large B-cell lymphoma. CD8+ tumor-infiltrating lymphocytes (TILs) exhaustion is a major barrier to effective tumor control in diffuse large B-cell lymphoma (DLBCL) and may consist of heterogeneous populations with different functional states. We profiled the CD8+TILs exhaustion heterogeneity and explored its clinical significance as well as the underlying mechanism through single-cell RNA sequencing (n = 7), bulk RNA sequencing (n = 3300), immunohistochemistry (n = 116), and reverse transcription-quantitative polymerase chain reaction (n = 95), and somatic mutation data (n = 48). Our results demonstrated that exhausted CD8+TILs in DLBCL were composed of progenitor and terminal states characterized by CCL5 and TUBA1B, respectively. High terminally exhausted CD8+TILs indicated an immunosuppressive tumor microenvironment, activated B-cell-like subtype, inferior prognosis, and poor response to immune checkpoint blockade therapy in DLBCL. Our study further demonstrated that the CD39/A2AR-related signaling may be the potential pathway that promoted the transition of progenitor toward terminally exhausted CD8+TILs in DLBCL. Furthermore, the CD39/A2AR-related pathway in DLBCL may be regulated by BATF and STAT3 in exhausted CD8+TILs, and MYD88 mutation in tumor cells. Our study highlights CD8+TILs exhaustion heterogeneity and its possible regulatory mechanism provides a novel prognostic indicator and can facilitate the optimization of individualized immunotherapy.