Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8+ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic-Cancer Orthotopic Mouse Model

Takashi Murakami; Yukihiko Hiroshima; Yong Zhang; Ming Zhao; Tasuku Kiyuna; Ho Kyoung Hwang; Kentaro Miyake; Yuki Homma; Ryutaro Mori; Ryusei Matsuyama; Takashi Chishima; Yasushi Ichikawa; Kuniya Tanaka; Michael Bouvet; Itaru Endo; Robert M Hoffman

doi:10.1002/jcb.26224

Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8⁺ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic-Cancer Orthotopic Mouse Model

J Cell Biochem. 2018 Jan;119(1):634-639. doi: 10.1002/jcb.26224. Epub 2017 Aug 11.

Authors

Takashi Murakami^{1

2

3}, Yukihiko Hiroshima^{1

2

3}, Yong Zhang¹, Ming Zhao¹, Tasuku Kiyuna^{1

2}, Ho Kyoung Hwang^{1

2}, Kentaro Miyake^{1

2}, Yuki Homma³, Ryutaro Mori³, Ryusei Matsuyama³, Takashi Chishima³, Yasushi Ichikawa³, Kuniya Tanaka³, Michael Bouvet², Itaru Endo³, Robert M Hoffman^{1

2}

Affiliations

¹ AntiCancer, Inc., San Diego, California.
² Department of Surgery, University of California, San Diego, California.
³ Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

PMID: 28628234
DOI: 10.1002/jcb.26224

Abstract

The present study determined the effect of the tumor-targeting strain Salmonella typhimurium A1-R (S. typhimurium A1-R) on CD8⁺ tumor-infiltrating lymphocytes (TILs) in a syngeneic pancreatic-cancer orthotopic mouse model. The effect of tumor-targeting S. typhimurium A1-R on CD8⁺ TILs was determined on the Pan02 murine pancreatic-adenocarcinoma implanted orthotopically in the pancreatic tail of C57BL/6 immunocompromised mice. Three weeks after orthotopic implantation, mice were randomized as follows G1: untreated control group (n = 8); and G2: S. typhimurium A1-R-treatment group (n = 8, 1 × 10⁷ colony forming units [CFU]/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor-volume ratio was defined as ratio of tumor volume on the 22nd day relative to the 1st day. The tumor volume ratio was significantly lower in the S. typhimurium A1-R-treated group (G2) (3.0 ± 2.8) than the untreated control (G1) (39.9 ± 30.7, P < 0.01). Hematoxylin and easin (H&E) staining on tumor sections was performed to evaluate tumor destruction which was classified according to the Evans grading system and found to be much greater in the S. typhimurium A1-R-treated mice (G2). Six mice in G1 had peritoneal dissemination, whereas no mice showed peritoneal dissemination in G2 (P < 0.01). Immunohistochemical staining with anti-mouse CD8⁺ antibody was performed in order to detect TILs determined by calculating the average number of CD8⁺ cells in three high power fields (200×) in the treated and untreated tumors. The TIL score was significantly higher in G2 (133.5 ± 32.2) than G1 (45.1 ± 19.4, P < 0.001). The present study demonstrates that S. typhimurium A1-R promotes CD8⁺ T cell infiltration and inhibition of tumor growth and metastasis. J. Cell. Biochem. 119: 634-639, 2018. © 2017 Wiley Periodicals, Inc.

Keywords: C57BL/6 MICE; CD8+ T CELLS; METASTASIS; ORTHOTOPIC MOUSE MODEL; PANCREATIC CANCER; Salmonella typhimurium A1-R; TUMOR INFILTRATION.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / immunology
Adenocarcinoma / pathology
Adenocarcinoma / therapy*
Animals
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / pathology
Immunity, Cellular*
Immunotherapy*
Mice
Mice, Nude
Neoplasm Metastasis
Neoplasms, Experimental / immunology
Neoplasms, Experimental / pathology
Neoplasms, Experimental / therapy*
Pancreatic Neoplasms / immunology
Pancreatic Neoplasms / pathology
Pancreatic Neoplasms / therapy*
Salmonella typhimurium / immunology*