Chronic inflammation often precedes malignant transformation and later drives tumor progression. Likewise, subversion of the immune system plays a role in tumor progression, with tumoral immune escape now well recognized as a crucial hallmark of cancer. Myeloid-derived suppressor cells (MDSC) are elevated in most individuals with cancer, where their accumulation and suppressive activity are driven by inflammation. Thus, MDSC may define an element of the pathogenic inflammatory processes that driven immune escape. The secreted alarmin HMGB1 is a pro-inflammatory partner, inducer and chaperone for many pro-inflammatory molecules that MDSC development. Therefore, in this study we examined HMGB1 as a potential regulator of MDSC. In murine tumor systems, HMGB1 was ubiquitous in the tumor microenvironment, activating the NF-κB signal transduction pathway in MDSC and regulating their quantity and quality. We found that HMGB1 foments the development of MDSC from bone marrow progenitor cells, contributing to their ability to suppress antigen-driven activation of CD4+ and CD8+ T cells. Further, HMGB1 increased MDSC-mediated production of IL-10, enhanced crosstalk between MDSC and macrophages and facilitated the ability of MDSC to down-regulate expression of the naive T cell homing receptor L-selectin. Overall, our results revealed a pivotal role for HMGB1 in the development and cancerous contributions of MDSC in cancer patients.

Programmed Death Ligand 1 (PD-L1, also known as B7 homolog 1 (B7-H1) or CD274) is a major obstacle to anti-tumor immunity because it (i) tolerizes/anergizes tumor-reactive T cells by binding to its receptor PD-1 (CD279); (ii) renders tumor cells resistant to CD8+ T cell and FasL-mediated lysis; and (iii) tolerizes T cells by reverse signalling through T cell-expressed CD80. PD-L1 is abundantly present in the tumor microenvironment where it is expressed by many malignant cells as well as by immune cells and vascular endothelial cells. The critical role of PD-L1 in obstructing anti-tumor immunity has been demonstrated in multiple animal models and in recent clinical trials. This article reviews the mechanisms by which PD-L1 impairs anti-tumor immunity and discusses established and experimental strategies for maintaining T cell activation in the presence of PD-L1-expressing cells in the tumor microenvironment.

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Purpose: Natural killer (NK)-cell-based immunotherapy may overcome obstacles to effective T-cell-based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC.Experimental Design: The ability of peripheral and tumorinfiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell-inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a smallmolecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells.Results: Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2 þ neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFb and production of H 2 O 2 . Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2 þ CD15 þ PMN-MDSC and CD14 þ monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFb and nitric oxide.Conclusions: The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.