Immune resistance orchestrated by the tumor microenvironment

Summary:  It is now little disputed that most if not all cancer cells express antigens that can be recognized by specific CD8+ T lymphocytes. However, a central question in the field of anti‐tumor immunity is why such antigen‐expressing tumors are not spontaneously eliminated by the immune system. While in some cases, this lack of rejection may be due to immunologic ignorance, induction of anti‐tumor T‐cell responses in many patients has been detected in the peripheral blood, either spontaneously or in response to vaccination, without accompanying tumor rejection. These observations argue for the importance of barriers downstream from initial T‐cell priming that need to be addressed to translate immune responses into clinical tumor regression. Recent data suggest that the proper trafficking of effector T cells into the tumor microenvironment may not always occur. T cells that do effectively home to tumor metastases are often found to be dysfunctional, pointing toward immunosuppressive mechanisms in the tumor microenvironment. T‐cell anergy due to insufficient B7 costimulation, extrinsic suppression by regulatory cell populations, inhibition by ligands such as programmed death ligand‐1, metabolic dysregulation by enzymes such as indoleamine‐2,3‐dioxygenase, and the action of soluble inhibitory factors such as transforming growth factor‐β have all been clearly implicated in generating this suppressive microenvironment. Identification of these downstream processes points to new therapeutic targets that should be manipulated to facilitate the effector phase of anti‐tumor immune responses in concert with vaccination or T‐cell adoptive transfer.