Department of Hepatobiliary and Pancreatic Surgery the Second Affiliated Hospital, School of Medicine, Zhejiang University, 310009, Hangzhou, China.
National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
Signal Transduct Target Ther. 2024 Nov 22;9(1):307. doi: 10.1038/s41392-024-02028-3.
The intricate tumor microenvironment presents formidable obstacles to the efficacy of adoptive T cell therapy in the management of solid tumors by limiting the infiltration and inducing exhaustion of the transferred T cells. Here, we developed a bacterial-based adjuvant approach that augments the efficacy of adoptive T-cell therapy for solid tumor treatment. Our study reveals that intratumor injection of E. coli MG1655 normalizes tumor vasculatures and reprograms tumor-associated macrophages into M1 phenotype that produce abundant CCL5, together facilitating tumor infiltration of adoptively transferred T cells. The depletion of tumor-associated macrophages or CCL5 neutralization in vivo leads to the significantly decreased solid tumor infiltration of adoptive T cells in the presence of bacteriotherapy. This combinatorial therapy, consisting of E. coli adjuvant and adoptive T-cell therapy, effectively eradicates early-stage melanoma and inhibits the progression of pancreatic tumors. Notably, this dual strategy also strengthened the distal tumor control capabilities of adoptive T-cell therapy through the induction of in situ tumor vaccination. This dual therapeutic approach involving bacterial therapy targeting the interior of solid tumors and adoptive T-cell therapy attacking the tumor periphery exhibits potent therapeutic efficacy in achieving the eradication of advanced-stage tumors, including melanoma and hepatocellular carcinoma, by converging attacks from both inside and outside the tumor tissues.
复杂的肿瘤微环境通过限制转移 T 细胞的浸润和诱导其衰竭，对过继性 T 细胞疗法治疗实体瘤的疗效构成了巨大障碍。在这里，我们开发了一种基于细菌的佐剂方法，增强了过继性 T 细胞疗法治疗实体瘤的疗效。我们的研究表明，在肿瘤内注射大肠杆菌 MG1655 可使肿瘤血管正常化，并将肿瘤相关巨噬细胞重新编程为产生丰富 CCL5 的 M1 表型，共同促进了过继性转移 T 细胞浸润肿瘤。体内耗尽肿瘤相关巨噬细胞或中和 CCL5 会导致在细菌治疗存在的情况下，过继性转移 T 细胞在实体瘤中的浸润明显减少。这种联合疗法由大肠杆菌佐剂和过继性 T 细胞疗法组成，可有效根除早期黑色素瘤并抑制胰腺肿瘤的进展。值得注意的是，这种双重策略还通过诱导原位肿瘤疫苗接种，增强了过继性 T 细胞疗法对远端肿瘤的控制能力。这种涉及细菌疗法靶向实体瘤内部和过继性 T 细胞疗法攻击肿瘤外围的双重治疗方法，通过从肿瘤内外同时攻击，展现出强大的治疗效果，可根除晚期肿瘤，包括黑色素瘤和肝细胞癌。
