Monoclonal antibodies (mAb) have revolutionized clinical medicine, especially in the field of cancer immunotherapy. The challenge now is to improve the response rates in the patients, as immunotherapy still fails for many patients. Strategies to enhance tumor cell death is a fundamental aim, but relevant model systems for human tumor immunology are lacking. Herein, we have developed a novel pre-clinical human immune three-dimensional (3D) tumor model (spheroids) to map the efficiency of tumor-specific isotypes for improved tumor cell killing. Different anti-CD20 Rituximab (RTX) isotypes alone or in combination, were evaluated for mediating complement-dependent cytotoxicity and antibody-dependent phagocytosis by human monocytic cells in 3D spheroids, in parallel with monolayer culture, of human CD20+ B-cell lymphoma. We show that the IgG3 variant of RTX has the greatest tumoricidal effect over other isotypes, mediating strong infiltration of monocytic effector cells into 3D spheroids. Hence, the human immune-3D tumor model is an attractive ex vivo system to help filter out mAbs for best efficacy in cancer immunotherapy.

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三维人体免疫肿瘤细胞模型揭示了同种型在基于抗体的免疫疗法中的重要性

单克隆抗体（mAb）彻底改变了临床医学，特别是在癌症免疫治疗领域。现在的挑战是提高患者的反应率，因为许多患者仍无法接受免疫治疗。增强肿瘤细胞死亡的策略是基本目标，但是缺乏用于人类肿瘤免疫学的相关模型系统。本文中，我们已经开发了一种新型的临床前人类免疫三维（3D）肿瘤模型（球体），以绘制肿瘤特异性同种型对改善肿瘤细胞杀伤力的作用。评估了单独的或组合的不同抗CD20利妥昔单抗（RTX）同种型在人类CD20 + B细胞淋巴瘤的单层培养中与人类单核细胞在3D球体中介导的补体依赖性细胞毒性和抗体依赖性吞噬作用。我们显示，RTX的IgG3变体对其他同种型具有最大的杀伤作用，介导单核效应细胞向3D球体的强烈浸润。因此，人类免疫3D肿瘤模型是一种有吸引力的离体系统，可帮助滤除mAb，从而在癌症免疫治疗中获得最佳疗效。