Glioma-infiltrating myeloid derived suppressor cells inhibit anti-tumor T cell responses

NEHA KAMRAN; HIKMAT ASSI; MARIANELA CANDOLFI; MARIELA MORENO AYALA; Y LI; PEDRO R LOWENSTEIN; MARIA G CASTRO

San Diego

Congreso; American Association of Cancer Research Annual Meeting; 2014

American Association of Cancer Research

Efficacy of immunotherapeutic approaches against glioma is limited by the immunosuppressive tumor microenvironment. Tumor derived TGF-β, IL-10 and Prostaglandin E2 along with the presence of regulatory T cells (Tregs) and tumor associated macrophages (TAMs) promote the immune escape in gliomas. Also, tumor derived factors induce the expansion of myeloid derived suppressor cells (MDSCs). MDSCs represent a heterogeneous population of myeloid cells at various stages of differentiation that have the potential to inhibit anti-tumor T cell responses. Herein we demonstrate the accumulation of MDSCs in GL26 brain tumor bearing mice. Absolute numbers of Ly-6G+ (Gr-1high) MDSCs showed a 200 fold increase within the tumor mass 28 days post-tumor implantation. In contrast, the numbers of Ly-6C+ (Gr-1low) MDSCs did not significantly change within the tumor microenvironment. While this massive influx of MDSCs was noted within intracranial tumors, the levels of Ly-6G+ or Ly-6C+ MDSCs did not increase in the tumor draining lymph nodes (dLNs), spleen, bone marrow or blood of intracranial tumor bearing mice. Mice bearing GL26 or B16-F0 tumors in the flank showed a ∼3 fold increased influx of Ly-6G+ MDSCs within the tumor mass, the spleen and circulating MDSCs. Ly-6G+ MDSCs isolated from the brain tumors and spleens of GL26 intracranial tumor bearing mice inhibited tumor antigen-specific CD8+ T cell proliferation and T cell proliferation mediated by CD3 ligation . On the other hand, Ly-6C+ MDSCs did not did not elicit inhibition of T cell proliferation. Preliminary experiments using tumor cells' conditioned media indicate that CXCR2 signaling mediates the migration of MDSCs in a transwell assay and suggest the possibility that it could mediate MDSCs' migration into the tumor microenvironment in vivo. Overall, our data shows that MDSCs accumulate within the glioma mass and inhibit tumor-specific T cell responses. Strategies that inhibit MDSC recruitment to the tumor microenvironment and/or block their activity may therefore enhance the T cell mediated tumor clearance and suppress glioma progression.