Navon Michal, Ben-Shalom Noam, Dadiani Maya, Mor Michael, Yefet Ron, Bakalenik-Gavry Michal, Chat Dana, Balint-Lahat Nora, Barshack Iris, Tsarfaty Ilan, Nili Gal-Yam Einav, Freund Natalia T
Department of Microbiology and Clinical Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel.
JCI Insight. 2025 May 22;10(10). doi: 10.1172/jci.insight.187392.
The presence of B cells in tumors is correlated with favorable prognosis and efficient response to immunotherapy. While tumor-reactive antibodies have been detected in several cancer types, identifying antibodies that specifically target tumor-associated antigens remains a challenge. Here, we investigated the antibodies spontaneously elicited during breast and lung cancer that bind the cancer-associated antigen MET. We screened patients with lung (n = 25) and breast (n = 75) cancer and found that 13% had antibodies binding to both the recombinant ectodomain of MET, and the ligand binding part of MET, SEMA. MET binding in the breast cancer cohort was significantly correlated with hormone receptor-positive status. We further conducted immunoglobulin sequencing of peripheral MET-enriched B cells from 6 MET-reactive patients. The MET-enriched B cell repertoire was found to be polyclonal and prone to non-IgG1 subclass. Nine monoclonal antibodies were cloned and analyzed, and these exhibited MET binding, low thermostability, and high polyreactivity. Among these, antibodies 87B156 and 69B287 effectively bound to tumor cells and inhibited MET-expressing breast cancer cell lines. Overall, our data demonstrate that some patients with breast and lung cancer develop polyreactive antibodies that cross-react with MET. These autoantibodies have a potential contribution to immune responses against tumors.
肿瘤中B细胞的存在与良好的预后以及对免疫治疗的有效反应相关。虽然在几种癌症类型中已检测到肿瘤反应性抗体，但鉴定特异性靶向肿瘤相关抗原的抗体仍然是一项挑战。在此，我们研究了乳腺癌和肺癌患者自发产生的与癌症相关抗原MET结合的抗体。我们对25例肺癌患者和75例乳腺癌患者进行了筛查，发现13%的患者产生的抗体既能结合重组MET胞外结构域，又能结合MET的配体结合部分SEMA。乳腺癌队列中的MET结合与激素受体阳性状态显著相关。我们进一步对6例MET反应性患者外周血中富集MET的B细胞进行了免疫球蛋白测序。发现富集MET的B细胞库是多克隆的，且倾向于非IgG1亚类。我们克隆并分析了9种单克隆抗体，这些抗体表现出MET结合、低热稳定性和高多反应性。其中，抗体87B156和69B287能有效结合肿瘤细胞并抑制表达MET的乳腺癌细胞系。总体而言，我们的数据表明，一些乳腺癌和肺癌患者会产生与MET发生交叉反应的多反应性抗体。这些自身抗体对肿瘤免疫反应有潜在贡献。
