title: Autologous reconstitution of human cancer and immune system in vivo.
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.
authors.affiliation: Department of Otolaryngology - Head & Neck Surgery, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Otolaryngology - Head & Neck Surgery, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Rupashree
authors.initials: R
authors.lastname: Sen
authors.affiliation: Department of Biomedical Engineering and The Institute for Computational Medicine, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Masica
authors.affiliation: Department of Biomedical Engineering and The Institute for Computational Medicine, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.affiliation: Bloomberg-Kimmel Institute for Cancer Immunotherapy, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.affiliation: Department of Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Vonn
authors.initials: V
authors.lastname: Walter
authors.affiliation: UNC Chapel Hill School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.affiliation: Department of Head & Neck - Endocrine Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Bloomberg-Kimmel Institute for Cancer Immunotherapy, SKCCC, Johns Hopkins Hospital, Baltimore, MD, USA.|Department of Otolaryngology - Head & Neck Surgery, VICC, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Young J
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D015789:HLA-A2 Antigen / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000473:pathology; D064593:Heterografts; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology* / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation / Q000276:immunology* / Q000473:pathology*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D019076:Transgenes; D014182:Transplantation, Autologous; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen
keywords: Immune response; Immunity; Immunology and Microbiology Section; STAT3; autologous reconstitution; head neck carcinoma; humanized mice; tumor microenvironment