CD8(+)TIL（肿瘤浸润淋巴细胞）耗竭异质性及其在弥漫性大 B 细胞淋巴瘤中的潜在机制的意义

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.