Patients with advanced
melanoma can develop spontaneous cellular and humoral responses to
tumor antigens. Understanding the failure of spontaneous or
vaccine-induced
tumor antigen-specific T-cell responses to promote the immunologic clearance of
melanomas is critical. Multiple mechanisms of
melanoma-induced immune escape, which are likely to cause the failure of the spontaneous or
vaccine-induced immune responses to promote
tumor regression in humans, have been elucidated. In addition, a number of negative factors in the tumor microenvironment dampen antitumor immune responses, including
cytokines (like
transforming growth factor-β or
interleukin-10), suppressive cells (regulatory T cells and myelosuppressive dendritic cells), defective antigen presentation by
tumor cells (
human leukocyte antigen or
T antigen expression loss, antigen processing machinery defects),
amino acid catabolizing
enzymes (indoleamine-2-3 dioxygenase, arginase), and immune inhibitory pathways (like
cytotoxic T-lymphocyte antigen 4/cluster of differentiation 28, programmed death 1/programmed death 1
ligand 1). This information has been used to develop a number of
therapies to specifically target these negative regulators of antimelanoma immune responses to enhance
tumor antigen-specific immune responses and to increase the likelihood of clinical benefits in patients with advanced
melanoma.