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Signal Transduction and Targeted Therapy

Signal Transduction and Targeted Therapy

IF: 40.8
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Remolding the tumor microenvironment by bacteria augments adoptive T cell therapy in advanced-stage solid tumors

Published:22 November 2024 DOI: 10.1038/s41392-024-02028-3
Zhu, Chaojie, Liu, Chao, Wu, Qing, Sheng, Tao, Zhou, Ruyi, Ren, En, Zhang, Ruizhe, Zhao, Zhengjie, Shi, Jiaqi, Shen, Xinyuan, Sun, Zhongquan, Mao, Zhengwei, He, Kaixin, Zhang, Lingxiao, Ding, Yuan, Gu, Zhen, Wang, Weilin, Li, Hongjun

Abstract

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.

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