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  • br Acknowledgement br Introduction Recent developments in ca

    2020-11-26


    Acknowledgement
    Introduction Recent developments in cancer immunotherapies have demonstrated durable responses, suggesting that effective immunotherapy would hold promise to improve patient outcome (Gunturu et al., 2013; Hodi et al., 2003; Lutz et al., 2011; Ribas et al., 2009). However, attempts to use immunotherapeutics as single agents have achieved only limited clinical success (Hodi et al., 2010; Le et al., 2013; Phan et al., 2003; Robert et al., 2011; Royal et al., 2010). The resistance to immunotherapy is in part mediated by the immunosuppressive microenvironment in the tumor tissue, and identification of such mechanisms is highly prudent in order to develop appropriate combination strategies. Multiple suppressive mechanisms have been implicated in the resistance to checkpoint blockade, including accumulation of myeloid-derived suppressor Apamin receptor (MDSCs) and increased expression of indoleamine 2,3-dioxygenase (IDO). MDSCs use several mechanisms to induce immunosuppression, such as production of arginase I (Arg1) and inducible nitric oxide synthase (iNOS), leading to T-cell inhibition (Gabrilovich and Nagaraj, 2009). MDSCs can also promote tumor cell proliferation, confer resistance to cytotoxic therapies, and facilitate metastatic dissemination and angiogenesis (Gabrilovich and Nagaraj, 2009). Therefore, high numbers of tumor-infiltrating MDSCs are often associated with high tumor burden and metastatic disease, leading to poor survival in cancer patients (Diaz-Montero et al., 2009). Therapeutic targeting of MDSCs might overcome immunosuppression to enhance responses to immunotherapy. Targeting of the colony stimulating factor-1 receptor (CSF-1R) has emerged as a strategy to ablate MDSCs or inhibit their tumor-promoting functions (Manthey et al., 2009; Patel and Player, 2009). CSF-1 is a cytokine frequently produced by several cancers, including melanoma, pancreatic cancer, and breast cancer (Priceman et al., 2010; Richardsen et al., 2015; Tarhini et al., 2012; Zhu et al., 2014). Secreted CSF-1 binds to the tyrosine kinase receptor CSF-1R on myeloid cells, which results in increased proliferation and differentiation of myeloid cells into MDSCs and M2 macrophages, and their recruitment into tumors (Caescu et al., 2015; Dai et al., 2002). Therefore, an immunosuppressive tumor microenvironment mediated by CSF-1 may limit the anti-tumor activity of tumor immunotherapy and lead to low response rates (Kerkar and Restifo, 2012). PLX647 is an analog of PLX3397, which is a potent CSF-1R inhibitor currently in clinical development as a single agent and in combination for the treatment of cancer patients. Recent work in preclinical models shows that CSF-1R inhibition inhibits the immunosuppressive tumor microenvironment and facilitates immune responses to cancer (Aharinejad et al., 2004; Coniglio et al., 2012; DeNardo et al., 2011; Mok et al., 2014; Priceman et al., 2010; Xu et al., 2013). Despite these findings, its relation with known suppressive mechanisms is unclear and what biomarkers would predict sensitivity to CSF-1R inhibition is not well defined. Here, we examine the possibility of circumventing IDO suppression by targeting MDSCs in IDO-expressing tumors. Indeed, while studying the role of IDO in the tumor microenvironment, we previously found that overexpression of IDO by tumor cells (B16-IDO) promotes the recruitment of large numbers of highly suppressive MDSCs (Holmgaard et al., 2015). We took advantage of this tumor model to examine the possibility of abolishing the suppressive effect of IDO by targeting MDSCs in IDO-expressing tumors. We studied the role of the MDSCs in mediating resistance to immunotherapies and to develop rationally designed combinatorial immunotherapeutic approaches through CSF-1R targeting. Our data demonstrate that CSF-1R blockade with PLX647 depletes suppressive MDSCs and delays tumor growth in the B16-IDO tumor model dominated by MDSCs, but not in the control B16 tumor model. Inhibition of CSF-1R signaling functionally blocks MDSCs and enhances anti-tumor T cell responses and therefore partially rescue immune suppression conferred by IDO expression. Thus, our data demonstrate a reversal of IDO induced immunosuppression by targeting MDSCs through CSF-1R blockade. Moreover, we demonstrate that targeting of CSF-1R sensitized the tumors to immunotherapy with Cytotoxic T Lymphocyte-Associated Protein-4 (CTLA-4), Programmed Cell Death Protein-1 (PD-1), or IDO blockade. Previous work suggests that IDO promotes immune suppression by direct action on effector T cells and/or regulatory T cells (Tregs). Our findings suggest that both T cells and MDSCs contribute to IDO suppressive effects and as a result provide a strong rationale to reprogram immunosuppressive MDSCs in the tumor microenvironment under conditions that can significantly improve the effects of other immunotherapeutic agents that target T cells and IDO. Supporting these findings, we find that CSF-1R blockade also potentiates antitumor responses to T cell checkpoint immunotherapy in other animal tumor models. Importantly, this potentiation was only seen in tumors highly infiltrated with suppressive MDSCs, suggesting that the presence of MDSCs could serve as a pre-treatment biomarker that could predict the efficacy of such combination in patients.