Over the last decade an increased understanding of the complex interaction between immune surveillance and tumor growth has led to major advances in the field of immunotherapy. This has broadened application of immunotherapy in various malignancies. The goal of immunotherapy is to harness the body’s immune system to recognize and target cancer. This chapter will highlight the basic principles of immunotherapy and describe the clinical application of immunotherapy in genitourinary malignancies.
PRINCIPLES OF CANCER IMMUNOLOGY
Innate and Adaptive Immunity
Innate and adaptive immunity are two facets of a healthy immune system required to mount an antitumor response. Innate immunity consists of natural barriers (skin, mucous membranes) along with defenses including neutrophils, natural killer cells, mast cells, dendritic cells, and macrophages. It is time-independent and usually the host’s nonspecific first line of defense. In contrast, adaptive immunity includes T and B lymphocytes and is time-dependent, specialized, reactive to specific antigens, and capable of immunological memory. Dendritic cells, a type of antigen-presenting cell (APC), function as a link between the innate and adaptive immune systems. After acquiring and processing antigens, dendritic cells mature and present foreign antigens, generally derived from pathogens or tumor cells, to the T cells of the adaptive immune system. After the T and B cells are primed by the dendritic cells, they exert their antitumor response in an antigen-specific manner through cell-mediated immunity and production of antibodies, respectively. The interaction between the T-cell receptor (on the T cell) and major histocompatibility antigen complex (MHC) on the APC constitutes an immune synapse and is required for activation of T cells. The cytotoxic activity of T cells is regulated by numerous stimulatory and inhibitory receptors whose activity is closely regulated by cytokines. In particular, because uncontrolled immune activation can lead to the development of autoimmunity, there exist numerous normally occurring checkpoints designed to dampen an immune response. Thus, checkpoint receptors on T cells are upregulated by cytokines released with immune activation, bind to their ligands, subsequently inhibit T cell function, and thereby dampen and limit the immune response. Two highly relevant inhibitory (checkpoint) transmembrane protein receptors on lymphocytes are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Both are expressed on lymphocytes (among other immune cells), upregulated by cytokines released following immune activation, and when bound to their ligand, downregulate immune responses. CTLA-4 activation and subsequent immune downregulation occur on binding B7-1 and B7-2 (CD80 and CD86) on the surface of APCs, while PD-1 binds to its ligand PD-L1, which is expressed on the surface of tumor cells and hematopoietic cells. The interaction between PD-1 and PD-L1 inhibits tumor lysis, enhances conversion of cytotoxic T cells to Treg cells, and causes peripheral T-cell exhaustion. These specific immune checkpoints are noteworthy because they have been successfully therapeutically targeted by checkpoint inhibitors, to eliminate this negative regulation, and allow an immune response to develop.