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Abstract
Pancreatic cancer is resistant to conventional therapeutic interventions, mainly due to abundant cancer stromal cells and poor immune cell infiltration. Here, we used a targeted cancer therapy approach based on attenuated Salmonella typhimurium engineered to express cytolysin A (ClyA) to target cancer stromal cells and cancer cells and treat pancreatic cancer in mice. Nude mice bearing subcutaneous or orthotopic human pancreatic cancers were treated with engineered S. typhimurium expressing ClyA. The tumor microenvironment was monitored to analyze stromal cell numbers, stromal cell marker expression, and immune cell infiltration. The attenuated bacteria accumulated and proliferated specifically in tumor tissues after intravenous injection. The bacteria secreted ClyA into the tumor microenvironment. A single dose of ClyA-expressing Salmonella markedly inhibited growth of pancreatic cancer both in subcutaneous xenograft- and orthotopic tumor-bearing nude mice. Histological analysis revealed a marked decrease in expression of stromal cell markers and increased immune cell (neutrophils and macrophages) infiltration into tumors after colonization by ClyA-expressing bacteria. ClyA-expressing S. typhimurium destroyed cancer stromal cells and cancer cells in mouse models of human pancreatic cancer. This approach provides a novel strategy for combining anticancer and anti-stromal therapy to treat pancreatic cancer.

Affiliations

Wenzhi Tan  1 , Mai Thi-Quynh Duong  2 , Chaohui Zuo  3 , Yeshan Qin  2 , Ying Zhang  2 , Yanxia Guo  1 , Yeongjin Hong  4 , Jin Hai Zheng  5 , Jung-Joon Min  6
1 School of Biomedical Sciences, Hunan University, Changsha, Hunan 410082, China.
2 Institute for Molecular Imaging and Theranostics, Chonnam National University Hwasun Hospital, Jeonnam 58128, Republic of Korea.
3 Department of Gastroduodenal and Pancreatic Surgery, Hunan Cancer Hospital, Changsha, Hunan 410013, China.
4 Department of Microbiology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
5 School of Biomedical Sciences, Hunan University, Changsha, Hunan 410082, China; Institute for Molecular Imaging and Theranostics, Chonnam National University Hwasun Hospital, Jeonnam 58128, Republic of Korea. Electronic address: jhzheng@hnu.edu.cn.
6 Institute for Molecular Imaging and Theranostics, Chonnam National University Hwasun Hospital, Jeonnam 58128, Republic of Korea; Department of Nuclear Medicine, Chonnam National University Hwasun Hospital, Jeonnam 58128, Republic of Korea. Electronic address: jjmin@jnu.ac.kr.