Oncotarget

Research Papers:

Tumor location impacts immune response in mouse models of colon cancer

Xianda Zhao, Lihua Li, Timothy Starr and Subbaya Subramanian _

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Oncotarget. 2017; 8:54775-54787. https://doi.org/10.18632/oncotarget.18423

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Abstract

Xianda Zhao1, Lihua Li1, Timothy K. Starr2 and Subbaya Subramanian1,3

1Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA

2Department of Obstetrics and Gynecology and Women’s Health, University of Minnesota Medical School, Minneapolis, MN, USA

3Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

Correspondence to:

Subbaya Subramanian, email: [email protected]

Keywords: colorectal cancer, immune profiles, immunotherapy, mouse models of cancer, orthotopic models

Received: March 21, 2017     Accepted: May 23, 2017     Published: June 09, 2017

ABSTRACT

Existing preclinical models of human colorectal cancer (CRC) that rely on syngeneic subcutaneous grafts are problematic, because of increasing evidence that the immune microenvironment in subcutaneous tissue is significantly different from the gastrointestinal tract. Similarly, existing orthotopic models that use a laparotomy for establishing grafts are also problematic, because the surgical procedure results in extensive inflammation, thereby creating a nonphysiologic tumor microenvironment. To facilitate the bench-to-bedside translation of CRC immunotherapy strategies, we developed a novel orthotopic model in mice that uses endoscopy-guided microinjection of syngeneic cancer cells. When we compared immune system infiltration, we found that tumors in the subcutaneous model had fewer T cells, B cells, and natural killer (NK) cells, but more immunosuppressive myeloid cells; in contrast, tumors in our orthotopic model had a higher number of tumor-infiltrating T cells, B cells, and NK cells, with fewer immunosuppressive myeloid cells. The number of immune-stimulating cytokines, such as interleukin (IL)-2, IL-6, interferon (IFN)-gamma, and granzyme B, was also higher in tumors in our model, as compared with the subcutaneous model. Those differences resulted in heightened sensitivity to immune checkpoint blockade therapy in our endoscopy-guided orthotopic CRC model. Our study indicates that tumor location affects immune response in CRC mouse models; choosing the appropriate preclinical model is important when testing immunotherapy in CRC.


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