Immunotherapy of cancer

Abstract

Major advances have been made in the field of immunology in the past two decades. A better understanding of the molecular and cellular mechanisms controlling the immune system has opened the door to many innovative and promising new cancer therapies that manipulate the immune response. For instance, toll-like receptor agonists have been shown to boost immune responses toward tumors. Also, a wide array of cell-based immunotherapies utilizing T cells, NK cells, and dendritic cells have been established. Furthermore, a rapidly expanding repertoire of monoclonal antibodies is being developed to treat tumors, and many of the available antibodies have demonstrated impressive clinical responses. Here, we examine some of these immunotherapeutic approaches currently in use or testing to treat cancer, and we examine available evidence with regards to mechanism and efficacy of these treatments.

Figure 1. Major cells of the innate and adaptive immune systems and their functions in response to a tumor cell

Grey boxes delineate the major cell types constituting the innate and adaptive immune systems. Arrows describe impacts of immune cells on each other or the tumor. Note that this is a very basic schematic designed to define interactions of relevance to the review, and numerous complex molecular interactions and minor immune cell subsets further influence these functions.

Figure 2. Minor subsets of T cells and their cytokine products

Distinct T cell subsets are shown with the major cytokines that they can produce to influence other immune cells or tumors.

Figure 3. Surface receptor interactions establishing the basis for tolerance and cytolytic responses by NK cells

NK cell activation is regulated by a balance of signals derived from activating and inhibitory surface receptors. Activating receptors recognize an array of cell surface molecules, some of which are expressed ubiquitously on the surfaces of other cells of the body. Inhibitory receptors, such as KIR, recognize MHC class I (MHC-I) molecules, which are expressed on the surface of virtually every normal cell of the body, while many tumor cells lack expression of this “self” molecule. KIR engagement with MHC-I triggers inhibitory signals (predominantly protein tyrosine phosphatase-based) within the NK cell that dominantly suppress activating receptor signals (predominantly protein tyrosine kinase-based) and result in tolerance. Upon encounter with a rare tumor cell lacking MHC-I (so-called “missing self”), the lack of inhibitory signaling at the cell contact interface triggers rapid and directed release of cytolytic granules toward the tumor target cell, which results in specific cytolysis of the target cell.