Article ; Online: Autologous reconstitution of human cancer and immune system in vivo.
2016 Volume 8, Issue 2, Page(s) 2053–2068
Abstract: ... xenotransplantation method to reconstitute the human tumor immune microenvironment in vivo. We were able ... that can potentially regulate the immune cells in our system, we silenced STAT3 signaling in the tumor compartment ... which were associated with slower tumor growth rate. We also used this novel system to characterize human ...
| 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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| MeSH term(s) | Animals ; Carcinoma, Squamous Cell/immunology ; Carcinoma, Squamous Cell/pathology ; Cell Line, Tumor ; HLA-A2 Antigen/genetics ; Head and Neck Neoplasms/immunology ; Head and Neck Neoplasms/pathology ; Heterografts ; Humans ; Lymphocytes, Tumor-Infiltrating/pathology ; Lymphocytes, Tumor-Infiltrating/physiology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mice, Transgenic ; Neoplasm Transplantation/immunology ; Neoplasm Transplantation/pathology ; Neoplasms/immunology ; Neoplasms/pathology ; Squamous Cell Carcinoma of Head and Neck ; Transgenes ; Transplantation, Autologous ; Tumor Microenvironment/immunology |
| Chemical Substances | HLA-A*02:01 antigen ; HLA-A2 Antigen |
| Language | English |
| Publishing date | 2016-12-20 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 2560162-3 |
| ISSN | 1949-2553 ; 1949-2553 |
| ISSN (online) | 1949-2553 |
| ISSN | 1949-2553 |
| DOI | 10.18632/oncotarget.14026 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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