B细胞在荷瘤小鼠PD-(L)1抗体治疗中的作用

侯俊雷; 杨学智; 董芬; 查皓然; 杨菲; 朱波

doi:10.16016/j.2097-0927.202401015

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B细胞在荷瘤小鼠PD-(L)1抗体治疗中的作用

基础医学 | 更新时间：2026-01-09

- B细胞在荷瘤小鼠PD-(L)1抗体治疗中的作用
- Role of B cells in anti-PD-(L)1 therapy in tumor bearing mice
- 陆军军医大学学报 2024年46卷第8期页码：804-814
- 作者机构：
  
  1.400037 重庆，陆军军医大学(第三军医大学)第二附属医院全军肿瘤研究所
  2.130062 长春，解放军第九六四医院放射科
  3.400054 重庆，重庆理工大学药学与生物工程学院
  4.100088 北京，解放军火箭军特色医学中心肿瘤科
- 作者简介：
  
  [朱波，E-mail: bo.zhu@tmmu.edu.cn ZHU Bo, E-mail: bo.zhu@tmmu.edu.cn
- 基金信息：
  
  国家自然科学基金面上项目(82272808)
- DOI：10.16016/j.2097-0927.202401015
  中图分类号： R392.12;R730.51;R739.5
- 收稿：2024-01-04，
  
  修回：2024-03-04，
  
  纸质出版：2024-04-30
- 稿件说明：
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侯俊雷, 杨学智, 董芬, 等. B细胞在荷瘤小鼠PD-(L)1抗体治疗中的作用[J]. 陆军军医大学学报, 2024,46(8):804-814.

Junlei HOU, Xuezhi YANG, Fen DONG, et al. Role of B cells in anti-PD-(L)1 therapy in tumor bearing mice[J]. Journal of Army Medical University, 2024, 46(8): 804-814.
侯俊雷, 杨学智, 董芬, 等. B细胞在荷瘤小鼠PD-(L)1抗体治疗中的作用[J]. 陆军军医大学学报, 2024,46(8):804-814. DOI： 10.16016/j.2097-0927.202401015.

Junlei HOU, Xuezhi YANG, Fen DONG, et al. Role of B cells in anti-PD-(L)1 therapy in tumor bearing mice[J]. Journal of Army Medical University, 2024, 46(8): 804-814. DOI： 10.16016/j.2097-0927.202401015.

摘要

目的

探讨肿瘤浸润性B细胞对程序性死亡受体(配体)1[programmed death (ligand) 1

PD-(L)1]抑制剂治疗效果的影响，阐明B细胞影响免疫治疗的潜在机制。

方法

通过使用公共数据库中的黑色素瘤患者免疫治疗队列，分析B细胞与无进展生存时间(progression-free survival，PFS)以及免疫治疗响应的关系；使用TC-1和B16-OVA肿瘤细胞对6~8周龄雌性C57BL/6小鼠的皮下及肝脏进行荷瘤，构建肿瘤模型。比较B细胞清除对PD-(L)1抗体治疗效果的影响；对第15天的TC-1肿瘤微环境(tumor microenvironment，TME)进行流式细胞术检测，明确T细胞的数目、功能及表型变化；通过流式细胞术及实时荧光定量聚合酶链式反应(quantitative real-time polymerase chain reaction，qPCR)检测B细胞表面分子以及细胞因子。

结果

基于ICBatlas公共数据库中的ERP105482数据分析，肿瘤中CD19高表达的黑色素瘤患者PFS较低表达者更长(753 d

95 d，

=0.3，95%

: 0.13~0.65，

=0.003)。B细胞在免疫治疗应答的患者中显著富集(

=0.01)。在小鼠TC-1肝脏荷瘤模型中，PD-(L)1抗体治疗后肿瘤质量明显减小(

＜0.01)，而B细胞的清除削弱了治疗效果。B细胞通过促进T细胞浸润和功能来增强PD-(L)1抗体治疗，且治疗后B细胞亚群发生变化，表现为PD-1低表达亚群增加(

＜0.01)。

结论

PD-(L)1抗体治疗后，B细胞亚群中PD-1表达的下降可能是B细胞促进PD-(L)1抗体治疗效果的潜在机制。

Abstract

Objective

To investigate the effect of tumor-infiltrating B cells on the therapeutic efficacy of programmed death ligand-1 [PD-(L)1] inhibitors and elucidate the potential mechanisms.

Methods

Based on immunotherapy cohorts for melanoma patients in public databases

the relationship of B cells with progression-free survival (PFS) and response to immune checkpoint inhibitors treatment was analyzed. TC-1 and B16-OVA cells were implanted subcutaneously and in the liver in 6-8-week-old female C57BL/6 mice to establish tumor xenograft models. The effect of B cell clearance on PD-(L)1 therapy was compared. Flow cytometry was performed on the 15th day of TC-1 tumor microenvironment (TME) to confirm the number

function and phenotypic changes of T cells. Flow cytometry and quantitative real-time polymerase chain reaction (qPCR) were used to detect B cell surface molecules and cytokines.

Results

Based on ERP105482 data from the ICBatlas public database

high CD19 expression in the tumors was associated with longer PFS in melanoma patients (753

95 d

=0.3

95%

: 0.13~0.65

=0.003). B cells were significantly enriched in immunotherapy-responsive patients (

=0.01). In a mouse TC-1 liver-loaded tumor model

PD-(L)1 antibody treatment reduced tumor mass (

0.01)

whereas B-cell clearance attenuated the therapeutic efficacy. B cells enhanced PD-(L)1 antibody treatment by promoting T cell infiltration and function

and the treatment resulted in changes in B cell subsets

as evidenced by an increase in PD-1 low-expressing subsets (

0.01).

Conclusion

After PD-(L)1 treatment

a decrease in PD-1 expression on B cell subsets might be one of the potential mechanisms by which B cells enhance the efficacy of PD-(L)1 therapy.

关键词

Keywords

references

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