ABSTRACT
Myeloid-derived suppressor cells (MDSC) are important regulators of immune responses in cancer. They represent a relatively stable form of pathologic activation of neutrophils and monocytes and are characterized by distinct transcriptional, biochemical, functional, and phenotypical features. The close association of MDSCs with clinical outcomes in cancer suggests that these cells can be an attractive target for therapeutic intervention. However, the complex nature of MDSC biology represents a substantial challenge for the development of selective therapies. Here, we discuss the mechanisms regulating MDSC development and fate and recent research advances that have demonstrated opportunities for therapeutic regulation of these cells. SIGNIFICANCE: MDSCs are attractive therapeutic targets because of their close association with negative clinical outcomes in cancer and established biology as potent immunosuppressive cells. However, the complex nature of MDSC biology presents a substantial challenge for therapeutic targeting. In this review, we discuss those challenges and possible solutions.
Subject(s)
Myeloid-Derived Suppressor Cells , Neoplasms , Humans , Monocytes , NeutrophilsABSTRACT
BACKGROUND: Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically "cold" tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated. METHODS: The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models. RESULTS: Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8+ T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models. CONCLUSION: Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.
Subject(s)
Dendritic Cells/immunology , Heterocyclic Compounds, 3-Ring/pharmacology , Killer Cells, Natural/immunology , Melanoma, Experimental/drug therapy , Stearic Acids/pharmacology , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists , Tumor Microenvironment/immunology , Adaptive Immunity , Adjuvants, Immunologic/pharmacology , Animals , Apoptosis , Cell Proliferation , Female , Humans , Immunotherapy , Male , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Ovalbumin/immunology , Rats, Sprague-Dawley , Tumor Cells, CulturedABSTRACT
To evade immune destruction, tumors exploit a wide range of immune escape mechanisms, including the induction of an immunosuppressive tumor microenvironment. This is mediated, in part, by amino acid degrading enzymes indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase, arginase 1 and arginase 2, which have emerged as key players in the regulation of tumor-induced immune tolerance. Here we describe how the expression of tryptophan- and arginine-degrading enzymes by tumor and tumor-infiltrating cells can hamper cancer-specific immune responses, and discuss how this knowledge is being exploited to develop new strategies for cancer immunotherapy.
Subject(s)
Arginase/metabolism , Immunotherapy/methods , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Neoplasms/therapy , Tryptophan Oxygenase/metabolism , Animals , Humans , Immunity , Molecular Targeted Therapy , Neoplasms/immunology , Tumor EscapeABSTRACT
Tryptophan degradation is an immune escape strategy shared by many tumors. However, cancer cells' compensatory mechanisms remain unclear. We demonstrate here that a shortage of tryptophan caused by expression of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) resulted in ATF4-dependent upregulation of several amino acid transporters, including SLC1A5 and its truncated isoforms, which in turn enhanced tryptophan and glutamine uptake. Importantly, SLC1A5 failed to be upregulated in resting human T cells kept under low tryptophan conditions but was enhanced upon cognate antigen T-cell receptor engagement. Our results highlight key differences in the ability of tumor and T cells to adapt to tryptophan starvation and provide important insights into the poor prognosis of tumors coexpressing IDO and SLC1A5. Cancer Res; 76(21); 6193-204. ©2016 AACR.
