The role of marginal zone macrophages and immuno-metabolism in tumor-driven MDSC development

Information

  • Research Project
  • 9685861
  • ApplicationId
    9685861
  • Core Project Number
    R01CA190449
  • Full Project Number
    5R01CA190449-05
  • Serial Number
    190449
  • FOA Number
    PA-13-302
  • Sub Project Id
  • Project Start Date
    12/1/2015 - 8 years ago
  • Project End Date
    4/30/2021 - 3 years ago
  • Program Officer Name
    KUO, LILLIAN S
  • Budget Start Date
    5/1/2019 - 5 years ago
  • Budget End Date
    4/30/2020 - 4 years ago
  • Fiscal Year
    2019
  • Support Year
    05
  • Suffix
  • Award Notice Date
    5/17/2019 - 5 years ago

The role of marginal zone macrophages and immuno-metabolism in tumor-driven MDSC development

Project Summary Tumor-driven myeloid-derived suppressor cell (MDSC) expansion in the marginal zone (MZ) of the spleen is critical for suppression of anti-tumor CD8+ T cell responses in vivo. In previously published data we reported that marginal zone-resident macrophages (MZ M?s) are critical sensors for cellular debris in circulation driving early tolerogenic responses and preventing auto-immunity. When we examined the spleens of tumor- bearing mice we found significant expansion of MDSCs in the MZ in contact with MZ M?s. Deletion of MZ M?s abrogated tumor-induced splenic IL-6 and CCL2 expression and MDSC expansion suggesting a previously unknown mechanistic relationship between MZ M?s and MDSCs. Moreover, we found MDSC activation induced differentiation and suppression required engagement of the GCN2 arm of the integrated stress response which, in turn, drove expression of the myeloid differentiation factor C/EBP?. In this proposal we hypothesize MZ M?-dependent expansion of MDSCs and GCN2-driven acquisition of suppressive function are related with MZ M?s providing the early signals driving MDSC recruitment to the MZ and activation. Our project will examine how tumors impact MZ M? expression of pro-MDSC factors and determine the functional relationship between this and GCN2 signal activation in MDSC precursors. If successful, the findings from this project would provide new insight into the contribution of microenvironment and stromal macrophages in tumor-mediated suppressive processes as well as provide novel therapeutic targets for cancer immuno-therapy.

IC Name
NATIONAL CANCER INSTITUTE
  • Activity
    R01
  • Administering IC
    CA
  • Application Type
    5
  • Direct Cost Amount
    1
  • Indirect Cost Amount
    0
  • Total Cost
    1
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    396
  • Ed Inst. Type
  • Funding ICs
    NCI:1\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    CMIB
  • Study Section Name
    Cellular and Molecular Immunology - B Study Section
  • Organization Name
    UNIVERSITY HEALTH NETWORK
  • Organization Department
  • Organization DUNS
    208469486
  • Organization City
    TORONTO
  • Organization State
    ON
  • Organization Country
    CANADA
  • Organization Zip Code
    M5G 2C4
  • Organization District
    CANADA