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Goyal, Girija

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Goyal

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Girija

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Goyal, Girija
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    Novel Role of PPAR-Gamma in GM-CSF Induced Anti-Tumor Immunity
    (2015-01-15) Goyal, Girija; Dranoff, Glenn; Dimitroff, Charles; Pillai, Shiv; Lerner, Adam
    Granulocyte macrophage colony stimulating factor (GM-CSF) mediates context dependent anti- or pro-inflammatory functions through cells of the myeloid lineage. GM-CSF signaling induces the expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ). We examined the role PPAR-γ in myeloid cells in the anti-tumor response to GVAX, a GM-CSF based cancer immunotherapy using the B16 model of murine melanoma. We found that selective loss of PPAR-γ in the myeloid lineage using LysM-Cre reduces the efficacy of GVAX which could not be explained by known mechanisms. RNASeq of GVAX draining lymph node identified an increase in regulatory T-cells markers such as FoxP3 and coinhibitory receptors CTLA-4 and TIGIT in LysM-Cre; PPAR-γ fl mice (PPAR-γ KO). We confirmed by flow cytometry that Treg frequency was indeed increased in PPAR-γ KO lymph node with a strong reduction seen in the ratio of CD8 T-cells to regulatory T cell (CD8:Treg). Treg recruiting chemokines CCL17 and CCL22 were upregulated in the draining lymph node. Importantly, tumors in PPAR-γ KO mice had a reduced CD8:Treg ratio explaining the loss in GVAX efficacy. Pharmacological activation or inactivation of PPAR-γ in GM-CSF treated human PBMC showed conservation of the role of PPAR-γ in regulating T-cell numbers in humans. PPAR-γ agonism in mice, using the FDA-approved small molecule ligand rosiglitazone (Rosi), improved CD8:Treg ratios in the vaccine draining lymph node and tumors. The gain-of-function data suggested the Rosi could be used as an adjunct to immunotherapy. All intratumoral Treg expressed high levels of CTLA-4 and TIGIT. Thus, we tested the impact of Rosi on the response to GVAX and anti-CTLA-4 combination therapy. We found that Rosi improved the tumor incidence and overall survival of tumor bearing mice treated with GVAX and anti-CTLA4. Our data have identified a novel role of PPAR-γ in myeloid cells in regulating Treg numbers. This pathway is conserved in humans as seen in ex-vivo studies of PBMC. Further, we provide preclinical evidence that Rosi can be used to improve immunotherapeutic responses by increasing the ratio between intratumoral effector and regulatory cells.
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    Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection
    (American Society for Microbiology, 2017) Rothchild, Alissa C.; Stowell, Britni; Goyal, Girija; Nunes-Alves, Cláudio; Yang, Qianting; Papavinasasundaram, Kadamba; Sassetti, Christopher M.; Dranoff, Glenn; Chen, Xinchun; Lee, Jinhee; Behar, Samuel M.
    ABSTRACT Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF−/−) are highly susceptible to infection with Mycobacterium tuberculosis, and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellular M. tuberculosis growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of M. tuberculosis. However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T cells also produce GM-CSF during M. tuberculosis infection. Early during infection, nonconventional iNKT cells and γδ T cells are the main source of GM-CSF, a role subsequently assumed by conventional CD4+ T cells as the infection progresses. M. tuberculosis-specific T cells producing GM-CSF are also detected in the peripheral blood of infected people. Under conditions where nonhematopoietic production of GM-CSF is deficient, T cell production of GM-CSF is protective and required for control of M. tuberculosis infection. However, GM-CSF is not required for T cell-mediated protection in settings where GM-CSF is produced by other cell types. Finally, using an in vitro macrophage infection model, we demonstrate that GM-CSF inhibition of M. tuberculosis growth requires the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Thus, we identified GM-CSF production as a novel T cell effector function. These findings suggest that a strategy augmenting T cell production of GM-CSF could enhance host resistance against M. tuberculosis.