The significance of CD8 tumor-infiltrating lymphocytes exhaustion heterogeneity and its underlying mechanism in 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 CD8TILs 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 CD8TILs in DLBCL were composed of progenitor and terminal states characterized by CCL5 and TUBA1B, respectively. High terminally exhausted CD8TILs 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 CD8TILs in DLBCL. Furthermore, the CD39/A2AR-related pathway in DLBCL may be regulated by BATF and STAT3 in exhausted CD8TILs, and MYD88 mutation in tumor cells. Our study highlights CD8TILs exhaustion heterogeneity and its possible regulatory mechanism provides a novel prognostic indicator and can facilitate the optimization of individualized immunotherapy.