Insights into Mechanisms of Immune Resistance in the Tumor Microenvironment through Molecular Profiling

Thomas F. Gajewski

Abstract Many patients with melanoma show spontaneous T cell responses against tumor antigens, and induction or amplification of these T cells responses can frequently be achieved through vaccination or adoptive T cell transfer. However, tumor responses as measured by tumor shrinkage remain infrequent. These observations have argued for analysis of the tumor microenvironment in metastatic melanoma for potential mechanisms of resistance to immune effector function at the level of the target tumor site. This review discusses two categories of regulation at the level of the tumor microenvironment, chemokine-mediated migration of effector T cells and active immune suppression, that have been identified through gene expression profiling of human specimens. Melanoma cell-intrinsic apoptosis also is discussed. The identification of these mechanisms points toward new strategies of intervention to consider for improving the clinical efficacy of T cell-based immunotherapy for cancer, and also suggest that molecular profiling of tumors might be used as a strategy for stratifying patients enrolled on immunotherapy clinical trials.

Keywords Melanoma, gene expression profiling, chemokines, T cells, immune suppression

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