美国Fred Hutchinson癌症中心Aaron M. Ring课题组在研究中取得进展。他们开发出检查点免疫治疗的体液决定因素。2025年7月23日出版的《自然》杂志发表了这项成果。

在这里，课题组对374名接受CPIs治疗的癌症患者和131名健康对照者进行了快速细胞外抗原分析，绘制了6172种细胞外和分泌蛋白（“外蛋白质组”）的自身抗体反应组。在全球范围内，接受CPI治疗的癌症患者具有不同的自身反应性，相对于对照个体升高，但随治疗变化最小。接受CPI治疗的患者的自身抗体特征显著地将他们与健康个体区分开来。

虽然特异性自身抗体与免疫相关不良事件的关联很少，但该研究组检测到许多个体自身抗体与治疗反应的优势比有很大的变化。这些包括免疫调节蛋白的自身抗体，如细胞因子、生长因子和免疫受体，以及肿瘤表面蛋白。几种自身抗体反应的功能评估表明，它们中和了它们的靶蛋白的活性，包括I型干扰素（IFN-I）、IL-6、OSM、TL1A、BMPR1A和BMPR2。在临床前肿瘤模型中模拟IFN-I和TL1A自身抗体的作用导致CPI疗效增强，这与它们在患者中的作用一致。总之，这些发现表明，外蛋白质组的自身抗体修饰CPI反应，并突出了可用于增强免疫治疗的治疗可操作途径。

据介绍，虽然细胞免疫在癌症检查点免疫治疗（CPI）中的作用已经确立，但抗体介导的体液免疫的作用尚未得到充分探讨。

附：英文原文

Title: Humoral determinants of checkpoint immunotherapy

Author: Dai, Yile, Aizenbud, Lilach, Qin, Kai, Austin, Matthew, Jaycox, Jillian R., Cunningham, Joseph, Wang, Eric Y., Zhang, Lin, Fischer, Suzanne, Carroll, Sean M., van Aggelen, Helen, Kluger, Yuval, Herold, Kevan C., Furchtgott, Leon, Kluger, Harriet M., Ring, Aaron M.

Issue&Volume: 2025-07-23

Abstract: Although the role of cellular immunity in checkpoint immunotherapy (CPI) for cancer is well established1,2, the effect of antibody-mediated humoral immunity is comparably underexplored. Here we used rapid extracellular antigen profiling3 to map the autoantibody reactome within a cohort of 374 patients with cancer treated with CPIs and 131 healthy control participants for autoantibodies to 6,172 extracellular and secreted proteins (the ‘exoproteome’). Globally, patients with cancer treated with CPIs had diverse autoreactivities that were elevated relative to control individuals but changed minimally with treatment. Autoantibody signatures in patients treated with CPI strikingly distinguished them from healthy individuals. Although associations of specific autoantibodies with immune-related adverse events were sparse, we detected numerous individual autoantibodies that were associated with greatly altered odds ratios for response to therapy. These included autoantibodies to immunomodulatory proteins, such as cytokines, growth factors and immunoreceptors, as well as tumour surface proteins. Functional evaluation of several autoantibody responses indicated that they neutralized the activity of their target proteins, which included type I interferons (IFN-I), IL-6, OSM, TL1A, and BMPR1A and BMPR2. Modelling the effects of autoantibodies to IFN-I and TL1A in preclinical mouse tumour models resulted in enhanced CPI efficacy, consistent with their effects in patients. In conclusion, these findings indicate that autoantibodies to the exoproteome modify CPI responses and highlight therapeutically actionable pathways that can be exploited to augment immunotherapy.

DOI: 10.1038/s41586-025-09188-4

Source: https://www.nature.com/articles/s41586-025-09188-4