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Independent mechanisms of T cell-suppression by subpopulations of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts
  1. Patrick L Raber1,2,
  2. Paul Thevenot1,
  3. Rosa Sierra1,
  4. Dorota Wyczechowska1,
  5. Maria E Ramirez1,
  6. Augusto Ochoa1,2,3,
  7. Cruz Velasco1 and
  8. Paulo C Rodriguez1,2
  1. Aff1 grid.279863.10000000089541233Department of Microbiology, Immunology and ParasitologyLouisiana State University Health Sciences Center New Orleans LA USA
  2. Aff2 grid.279863.10000000089541233Stanley S. Scott Cancer CenterLouisiana State University Health Sciences Center New Orleans LA USA
  3. Aff3 grid.279863.10000000089541233Department of PediatricsLouisiana State University Health Sciences Center New Orleans LA USA

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Meeting abstracts

Suppression of effector immune responses by the tumor microenvironment remains a major obstacle in the development of new therapies for cancer. The accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is a hallmark of malignancy-associated inflammation and a major mediator for the induction of T cell suppression by tumors. MDSC can be divided phenotypically into granulocytic (G-MDSC) and monocytic (Mo-MDSC) subgroups. Previous studies have identified several mechanisms of how MDSC impair T cell function; however, the specific role of these pathways in the inhibitory activity of MDSC subpopulations remains unclear. Therefore, we aimed to determine the effector mechanisms by which subsets of tumor-infiltrating MDSC block T cell function. Our results showed that G-MDSC displayed a higher ability to impair proliferation and expression of effector molecules in activated T cells, as compared to Mo-MDSC. This effect was validated using different transplantable tumor models. Interestingly, both MDSC subgroups inhibited T cells through nitric oxide (NO)-related pathways, but expressed different effector inhibitory mechanisms. Specifically, G-MDSC impaired T cells through the production of peroxynitrites (PNT), while Mo-MDSC suppressed by the release of NO. The production of PNT in G-MDSC depended on the expression of NADPH oxidase subunit gp91phox and endothelial NO synthase (eNOS), while inducible NO synthase (iNOS) mediated the generation of NO in Mo-MDSC. Deletion of eNOS and gp91phox or scavenging of PNT blocked the suppressive function of G-MDSC and induced anti-tumoral effects, without altering Mo-MDSC inhibitory activity. Furthermore, scavenging of NO or iNOS knockdown prevented Mo-MDSC function, but did not affect PNT production or T cell suppression by G-MDSC. Taken together, our data indicates the independent suppressive pathways by which tumor-infiltrating MDSC-subpopulations impair T cell responses. These findings may enable the development of potential therapies to specifically block particular MDSC subpopulations in cancer and other diseases characterized by the accumulation of MDSC subsets and T cell dysfunction.