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Identifying and Overcoming Immune Resistance Mechanisms in the Melanoma Tumor Microenvironment

Author's Affiliation: Department of Pathology and Department of Medicine, University of Chicago, Chicago, Illinois

Requests for reprints: Thomas F. Gajewski, Department of Pathology and Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. Phone: 773-702-4601; Fax: 773-702-3163; E-mail: tgajewsk{at}medicine.bsd.uchicago.edu.

The continually growing list of defined tumor antigens is broadening the potential applicability of tumor antigen-targeted cancer therapies. Although cancer vaccines and adoptive T-cell transfer have been shown to increase the frequency of circulating tumor antigen-specific T cells, these approaches cause clinical responses in a few patients. In melanoma, approximately one third of metastatic lesions contain activated T cells, including those specific for tumor antigens, arguing that the priming phase has occurred already in such individuals even without vaccination. These observations indicate that tumor resistance to immune destruction may dominate in many instances, arguing for a thorough analysis of the melanoma tumor microenvironment in individual patients. Recent work has suggested that T-cell anergy, the influence of CD4⁺CD25⁺ regulatory T cells, the expression of inhibitory ligands, such as PD-L1, and the activity of nutrient-catabolizing enzymes, such as indoleamine 2,3-dioxygenase, may be involved. Preclinical murine models have shown that interfering with each of these processes can translate into T-cell–mediated tumor control. Importantly, each of these targets is amenable to clinical manipulation. Clinical translation of these approaches to counter negative regulation of antitumor immunity should receive high priority.

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