肿瘤细胞治疗研究
英文原题：Intratumoral CD38(+)CD19(+)B cells associate with poor clinical outcomes and immunosuppression in patients with pancreatic ductal adenocarcinoma.
我们发现调节性 B 细胞样 CD38⁺ B 细胞浸润是胰腺导管腺癌（PDAC）的独立预后因素。
背景：肿瘤浸润B细胞广泛存在，提示其可能影响肿瘤行为。然而，胰腺导管腺癌（PDAC）中的B细胞异质性尚未得到研究。研究PDAC中的肿瘤浸润B细胞（TIL-B）有望发现新的治疗策略。 方法：我们开展单细胞RNA测序，研究PDAC中B细胞的异质性。在复旦大学附属肿瘤医院（FUSCC，n=147）和TCGA（n=176）队列中探索所识别CD38⁺ B细胞的预后和免疫学价值。采用流式细胞术分析CD38⁺ B细胞与其他免疫细胞的关系及其表型特征，并通过体内外实验评估CD38⁺ B细胞对抗肿瘤免疫的潜在影响。 研究发现：PDAC中CD38⁺ B细胞存在与不良临床病理特征及较差总生存期相关（p<0.001）。CD38⁺ B细胞浸润增加同时伴随NK细胞减少（p=0.021）和调节性T细胞增加（p=0.016）。分子特征分析显示，这些细胞高表达IL-10、IL-35、TGF-β、GZMB、TIM-1、CD5和CD21，证实其具有潜在调节性B细胞样特征。共培养实验显示，CD38⁺ B细胞来源的IL-10可抑制NK细胞细胞毒性（p<0.001）。最后，体内实验提示过继转移CD38⁺ B细胞会降低抗肿瘤免疫，而给予CD38抑制剂可抑制肿瘤生长（p<0.001）。 解释：我们发现，具有调节性B细胞样特征的CD38⁺ B细胞浸润是PDAC的独立预后因素。使用CD38抑制剂可能为PDAC免疫治疗提供新选择。 经费：本研究获得中国国家自然科学基金（U21A20374）、上海市科技重大项目（21JC1401500）、上海市教委科研创新项目（2019-01-07-00-07-E00057）、上海市卫健委卫生行业临床研究专项（20204Y0265）及上海市自然科学基金（23ZR1479300）支持。
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- , 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).
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