Inflammation and Immunosuppression in Lung Cancer

Summary

Principal Investigator: Cong Yan
Abstract: DESCRIPTION (provided by applicant): Chronic inflammation and immunosupression contribute to lung cancer formation. The long-term goal of this application is to identify the molecular and cellular mechanisms that control inflammation-induced tumorigenesis. Myeloid-derived suppressor cells (MDSCs) play a critical role in this process. MDSCs suppress T cell proliferation/function to subvert immune surveillance and prevent the immune system from eliminating tumor cells. Neutral lipid-derived hormones and their downstream nuclear receptors are keys to controlling the inflammation-induced MDSC surge and tumorigenesis. LAL hydrolyzes cholesteryl ester and triglycerides to generate free cholesterol and free fatty acids. Indeed, ablation of the lal gene resulted in systemic increase of MDSCs and immunosuppression of T cell proliferation/function in LAL knockout (lal-/-) mice. A defect in myelopoiesis with increased myeloid progenitor cells was observed in the lal-/- bone marrow. Adaptive bone marrow transplantation between wild type and lal-/- mice showed that both cell autonomous and tissue microenvironments contributed to abnormal MDSC development and homeostasis during LAL deficiency. To identify the molecular mechanism that controls these events, peroxisome proliferator-activated receptor gamma (PPAR?) appears to be a strong candidate. This is because 1) PPAR? is an anti-inflammatory agent;2) LAL-derived lipid metabolites serve as ligands to activate PPAR?;3) PPAR? negatively regulates inflammatory molecules that are up-regulated in lal-/- mice;4) PPAR? ligand treatment ameliorated inflammation and pathogenesis in lal-/- mice. The central hypothesis for the proposed studies is that the LAL/hormonal ligands/PPAR? axis in myeloid cells controls MDSCs development, homeostasis, immunosuppression and lung tumorigenesis. To test the central hypothesis and accomplish the goal of this application, two Specific Aims have been proposed. Aim 1 will test a working hypothesis that PPAR? ligands are required for balancing anti- and pro-inflammation cascades in vivo by regulating myelopoiesis, MDSC expansion and immunosuppression. This will be accomplished by reintroducing PPAR? ligands into lal-/- mice to rescue inflammatory and pathogenic phenotypes. Effect of PPAR? ligand treatment on Lewis lung carcinoma engrafted tumor growth and metastases in lal-/- mice will be investigated;Aim 2 will test a working hypothesis that PPAR? is required for balancing anti- and pro-inflammation cascades in vivo by regulating myelopoiesis, MDSC expansion and immunosuppression. This will be accomplished by overexpressing dnPPAR? in myeloid cells to inhibit the endogenous PPAR? function in c-fms-rtTA/(tetO)7-dnPPAR? bitransgenic mice to promote chronic inflammation and lung cancer. Since this model showed de novo tumorigenesis in the lung, bone marrow and MDSCs transplantation will be performed to test if MDSCs in this mouse model are directly responsible for tumorigenesis. Accomplishment of the proposed studies will elucidate the molecular mechanism by which the LAL/hormonal ligands/PPAR? axis controls anti-tumor adaptive immunity and pave the way for novel immunotherapy of lung cancer.
Funding Period: 2011-08-01 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis
    Lingyan Wu
    Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202 5188, USA
    Blood 119:115-26. 2012
  2. pmc Gene profile of myeloid-derived suppressive cells from the bone marrow of lysosomal acid lipase knock-out mice
    Cong Yan
    The Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
    PLoS ONE 7:e30701. 2012
  3. ncbi Myeloid-specific expression of Stat3C results in conversion of bone marrow mesenchymal stem cells into alveolar type II epithelial cells in the lung
    Cong Yan
    Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202 5188, USA
    Sci China Life Sci 55:576-90. 2012
  4. pmc Stat3 downstream gene product chitinase 3-like 1 is a potential biomarker of inflammation-induced lung cancer in multiple mouse lung tumor models and humans
    Cong Yan
    Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    PLoS ONE 8:e61984. 2013
  5. pmc Critical role of the mTOR pathway in development and function of myeloid-derived suppressor cells in lal-/- mice
    Xinchun Ding
    Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana
    Am J Pathol 184:397-408. 2014

Research Grants

Detail Information

Publications6

  1. pmc Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis
    Lingyan Wu
    Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202 5188, USA
    Blood 119:115-26. 2012
    ..These studies suggest that anti-inflammatory PPARγ in myeloid-lineage cells plays a key role in controlling pro-inflammatory cytokine synthesis, MDSC expansion, immunosuppression, and the development of cancer...
  2. pmc Gene profile of myeloid-derived suppressive cells from the bone marrow of lysosomal acid lipase knock-out mice
    Cong Yan
    The Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
    PLoS ONE 7:e30701. 2012
    ..Loss of the lysosomal acid lipase (LAL) function leads to expansion of myeloid-derived suppressive cells (MDSCs) that cause myeloproliferative neoplasm...
  3. ncbi Myeloid-specific expression of Stat3C results in conversion of bone marrow mesenchymal stem cells into alveolar type II epithelial cells in the lung
    Cong Yan
    Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202 5188, USA
    Sci China Life Sci 55:576-90. 2012
    ..The study supports the concept that activation of the Stat3 pathway in myeloid cells plays an important role in BMSC function, including homing, repopulating and converting into residential AT II epithelial cells in the lung...
  4. pmc Stat3 downstream gene product chitinase 3-like 1 is a potential biomarker of inflammation-induced lung cancer in multiple mouse lung tumor models and humans
    Cong Yan
    Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    PLoS ONE 8:e61984. 2013
    ..These models will facilitate identification of additional biomarkers to predict and verify lung cancer under various pathogenic conditions, which normally cannot be done in humans...
  5. pmc Critical role of the mTOR pathway in development and function of myeloid-derived suppressor cells in lal-/- mice
    Xinchun Ding
    Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana
    Am J Pathol 184:397-408. 2014
    ..The mTOR pathway may serve as a novel target to modulate the emergence of MDSCs in those pathophysiologic states in which these cells play an immunosuppressive role. ..

Research Grants30

  1. PPAR gamma Agonists for Lung Cancer Chemoprevention
    Robert Keith; Fiscal Year: 2013
    ..Our results will lead to a better understanding of the early stages of lung cancer and may lead to future human chemoprevention trials. ..
  2. The Role of PPARgamma in Lung Cancer Progression and Metastasis
    Howard Li; Fiscal Year: 2013
    ..Such an environment maximizes the potential for the applicant to establish a scientific niche from which an academic career can be constructed. ..
  3. Eicosanoids in Lung Cancer: Progression and Metastasis
    Raphael A Nemenoff; Fiscal Year: 2013
    ..Finally Aim 4 will examine eicosanoid profiles in human lung cancers and correlate this with clinical data and mutational status. ..
  4. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  5. Targeting Stat3 to Improve Immunotherapy
    HUA E YU; Fiscal Year: 2013
    ..abstract_text> ..
  6. Normal &Neoplastic Growth in the Brain
    Suzanne J Baker; Fiscal Year: 2013
    ..Integrated analyses within the group will identify common and unique signal transduction pathways in pediatric brain tumorigenesis. ..
  7. Sten Cell Gene Therapy of Breast Cancer
    ANDRE MICHAEL LIEBER; Fiscal Year: 2013
    ..Key findings will be validated in a second breast cancer model that involves 4T1 cells and BALB/c mice. ..
  8. TRAIL-expressing Recombinant Adenovirus Based Immunotherapy for RCC
    Thomas S Griffith; Fiscal Year: 2013
    ..The current proposal reflects our commitment to develop novel immunotherapies for RCC that can eliminate both primary tumors and distal metastases, thereby prolonging the survival of patients with advanced RCC. ..
  9. Targeting iNOS to inhibit myeloid-derived suppressor cells (MDSC) in melanoma
    ANDREW GREGORY SIKORA; Fiscal Year: 2013
    ..abstract_text> ..