Intratumoral CD38+CD19+B cells associate with poor clinical outcomes and immunosuppression in patients with pancreatic ductal adenocarcinomaResearch in context
Heng Zhu,
Jin Xu,
Wei Wang,
Bo Zhang,
Jiang Liu,
Chen Liang,
Jie Hua,
Qingcai Meng,
Xianjun Yu,
Si Shi
Affiliations
Heng Zhu
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
Jin Xu
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
Wei Wang
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
Bo Zhang
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
Jiang Liu
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
Chen Liang
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
Jie Hua
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
Qingcai Meng
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
Xianjun Yu
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Corresponding author. No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China.
Si Shi
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Corresponding author. No. 399 Lingling Road, Shanghai, 200032, China.
Summary: 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).
