Carcinogen-associated head and neck cancers are a heterogeneous group of aggressive cancers with a high recurrence rate and poor 5-year survival. Many of these cancers are T-cell inflamed but only a subset of patients respond to checkpoint blocking immunotherapy. Local immunosuppression mediated by both the tumor cells and other infiltrating immune cells are likely a major mechanism of resistance to immunotherapy. The mouse oral cancer (MOC) model includes genetically defined cell lines derived from carcinogen-induced tumors that generate tumors with variable T-cell inflamed phenotypes when transplanted into wild-type C57BL/6 mice. Mice bearing MOC1 tumors display a T-cell inflamed phenotype but do not significantly respond to PD-L1 checkpoint inhibition alone, which models a significant subset of human cancers from the oral cavity. Conversely, MOC2 tumors are non-T-cell inflamed. Using these MOC models, we have demonstrated an inverse relationship between accumulation of granulocytic MDSCs (gMDSCs) and effector immune cells (CD8/4+ T-cells, and NK cells) in the tumor microenvironment. Functionally, these gMDSCs suppressed CD8+ T-cell proliferation, IFNγ production, and antigen-specific killing. Depletion of these gMDSCs with a systemic anti-Ly6G antibody (1A8) did not change CD8/4+ T-cell or NK cell accumulation but restored tumor T-cell and NK cell activation and draining lymph node antigen-specific T-lymphocyte activation that was lost with tumor progression. Depletion of gMDSCs also significantly sensitized established MOC1 tumors to CTLA4-based checkpoint inhibition. CTLA-4 blockade alone induced tumor regression in a subset of mice and a marked delay in others. However, gMDSC depletion plus CTLA-4 blockade resulted in complete tumor rejection and development of immunologic memory in all treated mice. Peripheral gMDSCs were found to express the chemokine receptor CXCR2 but no other myeloid chemokine receptors, and expression of CXCR2 ligands CXCL1 and CXCL2 increased within the tumor microenvironment during tumor progression. Macrophage chemotaxis components CSF1R and CSF1 were not significantly expressed in these models. TCGA data analysis demonstrated an MDSC-rich gene expression profile in >60% of head and neck cancers, along with significant CTLA4, CXCR2, CXCL1, and CXCL8 (IL-8) expression within both HPV-positive and negative head and neck cancers. Functional inhibition or elimination of MDSCs from the tumor microenvironment may significantly reverse local immunosuppression and enhance responses to checkpoint inhibition in patients with head and neck cancer.

Citation Format: Paul Esteban Clavijo, Ellen Moore, Jianhong Chen, Ruth Davis, Carter Van Waes, Zhong Chen, Clint Allen. MDSC depletion combined with CTLA-4 blockade cause tumor regression in a syngeneic model of oral cavity cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3996. doi:10.1158/1538-7445.AM2017-3996