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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.

SUBMITTER: Fu J

PROVIDER: S-EPMC5356779 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Autologous reconstitution of human cancer and immune system in vivo.

Fu Juan J Sen Rupashree R Masica David L DL Karchin Rachel R Pardoll Drew D Walter Vonn V Hayes D Neil DN Chung Christine H CH Kim Young J YJ

Oncotarget 20170101 2

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 geneti ...[more]

PMID: 28008146

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Project description:BackgroundThe immunopathogenesis of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) remains incompletely understood, and we know of only 1 disease site-specific study of the underlying immunology; we recently showed that Mycobacterium tuberculosis culture positivity and increased neutrophils in the cerebrospinal fluid (CSF) of patients with tuberculous meningitis (TBM) are associated with TBM-IRIS. In this study we investigated inflammatory mediators at the disease site in patients with TBM-IRIS.MethodsWe performed lumbar puncture at 3-5 time points in human immunodeficiency virus (HIV)-infected patients with TBM (n = 34), including at TBM diagnosis, at initiation of antiretroviral therapy (ART) (day 14), 14 days after ART initiation, at presentation of TBM-IRIS, and 14 days thereafter. We determined the concentrations of 40 mediators in CSF (33 paired with blood) with Luminex or enzyme-linked immunosorbent assays. Findings were compared between patients who developed TBM-IRIS (n = 16) and those who did not (TBM-non-IRIS; n = 18).ResultsAt TBM diagnosis and 2 weeks after ART initiation, TBM-IRIS was associated with severe, compartmentalized inflammation in the CSF, with elevated concentrations of cytokines, chemokines, neutrophil-associated mediators, and matrix metalloproteinases, compared with TBM-non-IRIS. Patients with TBM-non-IRIS whose CSF cultures were positive for M. tuberculosis at TBM diagnosis (n = 6) showed inflammatory responses similar to those seen in patients with TBM-IRIS at both time points. However, at 2 weeks after ART initiation, S100A8/A9 was significantly increased in patients with TBM-IRIS, compared with patients with TBM-non-IRIS whose cultures were positive at baseline.ConclusionsA high baseline M. tuberculosis antigen load drives an inflammatory response that manifests clinically as TBM-IRIS in most, but not all, patients with TBM. Neutrophils and their mediators, especially S100A8/A9, are closely associated with the central nervous system inflammation that characterizes TBM-IRIS.

Dataset Information

Autologous reconstitution of human cancer and immune system in vivo.

Publications

Autologous reconstitution of human cancer and immune system in vivo.

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