Department of Medicine, Division of Dermatology, University of California, Los Angeles, Los Angeles, CA, United States.
Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA, United States.
Front Immunol. 2023 Jun 26;14:1176994. doi: 10.3389/fimmu.2023.1176994. eCollection 2023.
Increased 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.
We used transcriptional analysis and clinical outcomes from patients treated with ICI or MAPKi therapies to delineate immune mechanisms driving tumor response.
We discovered response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with significantly higher clonal diversity than MAPKi. Our 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.
Response 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.
在对免疫检查点抑制剂（ICI）或 MAPK 通路抑制剂（MAPKi）治疗有反应的黑色素瘤患者的肿瘤中，观察到 T 细胞浸润增加和干扰素γ（IFNγ）途径激活。然而，ICI 后持久肿瘤控制的比率几乎是 MAPKi 的两倍，这表明在对 ICI 治疗有反应的患者中可能存在其他机制，这些机制有利于抗肿瘤免疫。
我们使用转录分析和接受 ICI 或 MAPKi 治疗的患者的临床结果来描绘驱动肿瘤反应的免疫机制。
我们发现，对 ICI 的反应与 CXCL13 驱动的 CXCR5+B 细胞的募集有关，其克隆多样性明显高于 MAPKi。我们的数据表明，抗 PD1 而非 MAPKi 治疗可增加人外周血单核细胞中 CXCL13 的产生。更高的 B 细胞浸润和 B 细胞受体（BCR）多样性允许 B 细胞呈递多种肿瘤抗原，从而导致 ICI 治疗后滤泡辅助 CD4 T 细胞（Tfh）和肿瘤反应性 CD8 T 细胞的激活。与具有一个或没有 BCR 多样性和 IFNγ途径评分的患者相比，ICI 后 BCR 多样性和 IFNγ途径评分较高与患者的生存时间显著延长相关。
对 ICI 的反应，而不是对 MAPKi 的反应，取决于 CXCR5+B 细胞向肿瘤微环境的募集及其对滤泡辅助和细胞毒性、肿瘤反应性 T 细胞的有效肿瘤抗原呈递。我们的研究强调了 CXCL13 和基于 B 细胞的策略的潜力，以提高接受 ICI 治疗的黑色素瘤患者持久反应的比率。
