Intratumoral CD38+CD19+B cells associate with poor clinical outcomes and immunosuppression in patients with pancreatic ductal adenocarcinoma

Abstract

Background: The widespread involvement of tumor-infiltrating B cells highlights their potential role in tumor behavior. However, B cell heterogeneity in PDAC remains unexplored. Studying TIL-Bs in PDAC aims to identify new treatment strategies.

Methods: We performed single-cell RNA sequencing to study the heterogeneity of B cells in PDAC. The prognostic and immunologic value of the identified CD38⁺ B cells was explored in FUSCC (n = 147) and TCGA (n = 176) cohorts. Flow cytometry was conducted to characterize the relationship between CD38⁺ B cells and other immune cells, as well as their phenotypic features. In vitro and in vivo experiments were performed to assess the putative effect of CD38⁺ B cells on antitumor immunity.

Findings: The presence of CD38⁺ B cells in PDAC was associated with unfavorable clinicopathological features and poorer overall survival (p < 0.001). Increased infiltration of CD38⁺ B cells was accompanied by reduced natural killer (NK) cells (p = 0.021) and increased regulatory T cells (p = 0.016). Molecular profiling revealed high expression of IL-10, IL-35, TGF-β, GZMB, TIM-1, CD5 and CD21, confirming their putative regulatory B cell-like features. Co-culture experiments demonstrated suppression of NK cell cytotoxicity by CD38⁺ B cell-derived IL-10 (p < 0.001). Finally, in vivo experiments suggested adoptive transfer of CD38⁺ B cells reduced antitumor immunity and administration of a CD38 inhibitor hampered tumor growth (p < 0.001).

Interpretation: We discovered regulatory B cell-like CD38⁺ B cell infiltration as an independent prognostic factor in PDAC. The use of CD38 inhibitor may provide new possibilities for PDAC immunotherapy.

Funding: This study was supported by the National Natural Science Foundation of China (U21A20374), Shanghai Municipal Science and Technology Major Project (21JC1401500), Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), Special Project for Clinical Research in the Health Industry of the Shanghai Health Commission (No. 20204Y0265) and Natural Science Foundation of Shanghai (23ZR1479300).

Keywords: CD38(+)CD19(+) B cell; Clinical outcome; Immunosuppression; Immunotherapy; Pancreatic ductal adenocarcinoma.