Oncotarget

Research Papers: Immunology:

Autologous reconstitution of human cancer and immune system in vivo

Juan Fu, Rupashree Sen, David L. Masica, Rachel Karchin, Drew Pardoll, Vonn Walter, D. Neil Hayes, Christine H. Chung and Young J. Kim _

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Oncotarget. 2017; 8:2053-2068. https://doi.org/10.18632/oncotarget.14026

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Abstract

Juan Fu1, Rupashree Sen1, David L. Masica2, Rachel Karchin2,3, Drew Pardoll3, Vonn Walter4, D. Neil Hayes5, Christine H. Chung6 and Young J. Kim3,7

1 Department of Otolaryngology - Head & Neck Surgery, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA

2 Department of Biomedical Engineering and The Institute for Computational Medicine, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA

3 Bloomberg-Kimmel Institute for Cancer Immunotherapy, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA

4 Department of Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA

5 UNC Chapel Hill School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

6 Department of Head & Neck - Endocrine Oncology, Moffitt Cancer Center, Tampa, FL, USA

7 Department of Otolaryngology - Head & Neck Surgery, VICC, Vanderbilt University Medical Center, Nashville, TN, USA

Correspondence to:

Young J. Kim, email:

Keywords: tumor microenvironment, autologous reconstitution, STAT3, humanized mice, head neck carcinoma, Immunology and Microbiology Section, Immune response, Immunity

Received: August 19, 2016 Accepted: December 13, 2016 Published: December 19, 2016

Abstract

Correlative studies from checkpoint inhibitor trials have indicated that better understanding of human leukocytic trafficking into the human tumor microenvironment can expedite the translation of future immune-oncologic agents. In order to directly characterize signaling pathways that can regulate human leukocytic trafficking into the tumor, we have developed a completely autologous xenotransplantation method to reconstitute the human tumor immune microenvironment in vivo. We were able to genetically mark the engrafted CD34+ bone marrow cells as well as the tumor cells, and follow the endogenous leukocytic infiltration into the autologous tumor. To investigate human tumor intrinsic factors that can potentially regulate the immune cells in our system, we silenced STAT3 signaling in the tumor compartment. As expected, STAT3 signaling suppression in the tumor compartment in these autologously reconstituted humanized mice showed increased tumor infiltrating lymphocytes and reduction of arginase-1 in the stroma, which were associated with slower tumor growth rate. We also used this novel system to characterize human myeloid suppressor cells as well as to screen novel agents that can alter endogenous leukocytic infiltration into the tumor. Taken together, we present a valuable method to study individualized human tumor microenvironments in vivo without confounding allogeneic responses.


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