Table_4_Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors.xlsx

IntroductionIncreased T cell infiltration and interferon gamma (IFNγ) pathway activation are seen in tumors of melanoma patients who respond to ICI (immune checkpoint inhibitor) or MAPK pathway inhibitor (MAPKi) therapies. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi, suggesting that additional mechanisms may be present in patients responding to ICI therapy that are beneficial for anti-tumor immunity.
MethodsWe used transcriptional analysis and clinical outcomes from patients treated with ICI or MAPKi therapies to delineate immune mechanisms driving tumor response.
ResultsWe discovered response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with significantly higher clonal diversity than MAPKi. Our in vitro data indicate that CXCL13 production was increased in human peripheral blood mononuclear cells by anti-PD1, but not MAPKi, treatment. Higher B cell infiltration and B cell receptor (BCR) diversity allows presentation of diverse tumor antigens by B cells, resulting in activation of follicular helper CD4 T cells (Tfh) and tumor reactive CD8 T cells after ICI therapy. Higher BCR diversity and IFNγ pathway score post-ICI are associated with significantly longer patient survival compared to those with either one or none.
ConclusionsResponse to ICI, but not to MAPKi, depends on the recruitment of CXCR5+ B cells into the tumor microenvironment and their productive tumor antigen presentation to follicular helper and cytotoxic, tumor reactive T cells. Our study highlights the potential of CXCL13 and B cell based strategies to enhance the rate of durable response in melanoma patients treated with ICI.

引言 接受免疫检查点抑制剂（immune checkpoint inhibitor，ICI）或丝裂原活化蛋白激酶通路抑制剂（MAPK pathway inhibitor，MAPKi）治疗的黑色素瘤患者肿瘤组织中，可见T细胞浸润增加与干扰素γ（interferon gamma，IFNγ）通路激活。然而，ICI治疗后实现长期肿瘤控制的比例几乎为MAPKi治疗的两倍，这提示ICI治疗应答患者体内可能存在额外的、有益于抗肿瘤免疫的机制。
方法 本研究纳入接受ICI或MAPKi治疗的患者的转录组分析数据与临床结局，以阐明驱动肿瘤应答的免疫机制。
结果 本研究发现，相较于MAPKi治疗，ICI治疗应答与CXCL13介导的CXCR5+B细胞招募显著相关，且后者的克隆多样性显著更高。体外实验数据显示，抗PD-1治疗可上调人外周血单个核细胞（peripheral blood mononuclear cells，PBMC）中CXCL13的表达，但MAPKi治疗无此效果。更高水平的B细胞浸润与B细胞受体（B cell receptor，BCR）多样性，可使B细胞呈递多样化的肿瘤抗原，进而在ICI治疗后激活滤泡辅助性CD4 T细胞（follicular helper CD4 T cells，Tfh）与肿瘤反应性CD8 T细胞。相较于仅具备其中一项或两项均不具备的患者，ICI治疗后更高的BCR多样性与IFNγ通路评分，与患者更长的生存期显著相关。
结论 ICI治疗（而非MAPKi治疗）的应答依赖于CXCR5+B细胞向肿瘤微环境（tumor microenvironment）的招募，以及这些细胞向滤泡辅助性T细胞与细胞毒性肿瘤反应性T细胞呈递有效肿瘤抗原的能力。本研究凸显了基于CXCL13与B细胞的策略，在提升接受ICI治疗的黑色素瘤患者长期应答率方面的应用潜力。