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, Young J. Kim

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2053-2068
Number of pages16
JournalOncotarget
Volume8
Issue number2
DOIs
StatePublished - 2017

Keywords

  • Autologous reconstitution
  • Head neck carcinoma
  • Humanized mice
  • Immune response
  • Immunity
  • Immunology and Microbiology Section
  • STAT3
  • Tumor microenvironment

ASJC Scopus subject areas

  • Oncology

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