Introduction

The large body of accumulated evidence indicating that many, if not most, cancers express antigens that can be recognized by T cells of the immune system has led to a critical question in the field of antitumor immunity. Namely, why are antigen-expressing tumors not spontaneously eliminated through a T cell-mediated immune response? While there are numerous potential mechanisms that could explain this failure, much focus during the past decade has been on the presumption of immu-nologic ignorance. If a growing tumor fails to prime a tumor antigen-specific T cell response de novo, then active immunization of patients, or adoptive therapy of tumor antigen-specific T cells, should bypass this putative block and achieve tumor

Department of Pathology and Department of Medicine, Section of Hematology/Oncology University of Chicago, Chicago, IL, USA

E. Yefenof (ed.), Innate and Adaptive Immunity in the Tumor Microenvironment. © Springer 2008

regression. However, these approaches have met with limited therapeutic success, and it has become clear that increasing the frequencies of functional antitumor T cells is not always sufficient to obtain a clinical response [1, 2]. In addition, spontaneous priming of an antitumor immune response has been observed in patients with melanoma and other cancers, as detected either at the T cell level using peptide/HLA tetramer staining or specific IFN-g production [1, 3, 4], or at the humoral level by measuring antibodies specific for human tumor cells [5, 6]. Collectively, these and other similar observations have suggested that resistance to an antitumor immune response may frequently occur downstream from immune recognition and initial lymphocyte priming, likely at the level of the tumor microenvironment. Gaining a thorough understanding of the tumor microenvironment as it relates to the host immune response has thus become a significant priority. Gene expressing profiling of metastatic tumor sites in patients with melanoma has provided a rich source of information that is beginning to be confirmed mechanistically in preclinical and clinical contexts. Additional detailed understanding of molecular features of the tumor cells themselves is providing another level of information that highlights alternative mechanisms of immune resistance. These analyses are now shedding light on new potential interventions designed to overcome these mediators of immune escape at the level of the tumor microenvironment, and also is suggesting features that could guide patient selection in the setting for eligibility of T cell-based immunotherapy clinical trials.

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