Data_Sheet_3_Sensitization of Tumors for Attack by Virus-Specific CD8+ T-Cells Through Antibody-Mediated Delivery of Immunogenic T-Cell Epitopes.PDF

Anti-tumor immunity is limited by a number of factors including the lack of fully activated T-cells, insufficient antigenic stimulation and the immune-suppressive tumor microenvironment. We addressed these hurdles by developing a novel class of immunoconjugates, Antibody-Targeted Pathogen-derived Peptides (ATPPs), which were designed to efficiently deliver viral T-cell epitopes to tumors with the aim of redirecting virus-specific memory T-cells against the tumor. ATPPs were generated through covalent binding of mature MHC class I peptides to antibodies specific for cell surface-expressed tumor antigens that mediate immunoconjugate internalization. By means of a cleavable linker, the peptides are released in the endosomal compartment, from which they are loaded into MHC class I without the need for further processing. Pulsing of tumor cells with ATPPs was found to sensitize these for recognition by virus-specific CD8+ T-cells with much greater efficiency than exogenous loading with free peptides. Systemic injection of ATPPs into tumor-bearing mice enhanced the recruitment of virus-specific T-cells into the tumor and, when combined with immune checkpoint blockade, suppressed tumor growth. Our data thereby demonstrate the potential of ATPPs as a means of kick-starting the immune response against “cold” tumors and increasing the efficacy of checkpoint inhibitors.

抗肿瘤免疫受多种因素制约，包括完全活化T细胞（T-cell）的缺失、抗原刺激不足以及免疫抑制性肿瘤微环境。我们通过开发一类新型免疫缀合物（immunoconjugates）——抗体靶向病原体衍生肽（Antibody-Targeted Pathogen-derived Peptides，ATPPs）——攻克了上述障碍：该类缀合物可将病毒T细胞表位高效递送至肿瘤，以重定向病毒特异性记忆T细胞靶向肿瘤组织。ATPPs通过将成熟的主要组织相容性复合体I类（MHC class I）肽段与靶向细胞表面表达的肿瘤抗原的抗体共价结合制备而成，该抗原可介导免疫缀合物的内吞摄取。借助可裂解接头（cleavable linker），肽段会在内体区室（endosomal compartment）中释放，随后可直接装载至MHC I类分子，无需额外的蛋白加工过程。研究发现，用ATPPs脉冲处理肿瘤细胞，可使其被病毒特异性CD8+ T细胞（CD8+ T-cell）识别的敏感性显著提升，其效率远高于游离肽段的外源负载方式。向荷瘤小鼠全身注射ATPPs，可增强病毒特异性T细胞向肿瘤微环境的募集；若与免疫检查点阻断（immune checkpoint blockade）联合使用，则可有效抑制肿瘤生长。综上，本研究数据证实了ATPPs作为启动针对“冷”肿瘤（cold tumors）的免疫应答、提升免疫检查点抑制剂（checkpoint inhibitors）疗效的手段的应用潜力。