Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer–derived antibodies exhibited acidic pH–selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.

中文翻译：

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核酸触发的肿瘤免疫通过肿瘤驱动的表位扩散传播 pH 选择性治疗抗体

经常指出体液肿瘤免疫的重要作用；然而，优势抗原和发育机制的精确概况仍然难以捉摸。我们系统地研究了在人类癌症中发现的显性瘤内免疫球蛋白克隆的体液抗原。我们发现大约一半的相应抗原被限制在带强烈和密集负电荷的聚合物中，导致抗体同时对密集硫酸化糖胺聚糖 (dsGAG) 和核酸 (NA) 产生反应。这些抗 dsGAG/NA 抗体通过 NAs 的先天免疫的肿瘤内免疫驱动力成熟和扩展。这些源自人类癌症的抗体对两种抗原均表现出酸性 pH 选择性亲和力，并对多种人类肿瘤细胞表现出特异性反应性。抗体-药物偶联物通过靶向细胞表面 dsGAG 抗原在体内对多种癌症发挥治疗作用。这项研究揭示了肿瘤内免疫反应会繁殖以肿瘤为导向的免疫球蛋白克隆，并展示了一种普遍治疗人类恶性肿瘤的新治疗方式。