Since the original reports of Jenner over two centuries ago, prophylactic vaccination against infectious diseases has been one of the most influential medical interventions. Cancer vaccination, an immunotherapy approach applied to patients with established cancer, has tremendous potential based on the ability of both T cells and antibodies to specifically recognize cancer antigens and kill cancer cells expressing these antigens. However, at the time of this writing, only one human cancer vaccine has received U.S. Food and Drug Administration (FDA) approval, despite multiple Phase III clinical trials over the past two decades. Despite the clinical failures of cancer vaccines to date, continuing molecular definition of tumor-specific and tumor-selective antigens, new vaccine platforms that selectively target and activate dendritic cells, and preclinical results with combinations of vaccination together with other immune modulators have generated renewed optimism that cancer vaccination will ultimately take its place among the pantheon of cancer therapies.

As cancer genetics and genomics have exploded over the past decade, it is now quite clear that altered genetic and epigenetic features of tumor cells indeed result in a distinct tumor antigen profile. Overexpression of “oncogenic” growth factor receptor tyrosine kinases such as HER2/Neu and epidermal growth factor receptor (EGFR) via epigenetic mechanisms has provided clinically relevant targets for one arm of the immune system—antibodies. ^6,7 Indeed, monoclonal antibodies are the fastest growing single class of cancer therapeutics based on successful new FDA approvals. In striking contrast, cellular immunotherapy of cancer has been quite disappointing in establishing therapeutic success in clinical trials to date. Emerging insights about the nature of the interaction between the cancer and the immune system have led us to understand why cell-based cancer immunotherapy approaches such as therapeutic vaccines have been less potent against established cancer than originally imagined. In general, we have learned that tumors employ mechanisms of tolerance induction to turn off T cells specific for tumor-associated antigens. Oncogenic pathways in tumors result in the elaboration of factors that organize the tumor microenvironment in ways that are quite hostile to antitumor immune responses.

Not only is the cancer capable of inducing potent tolerance among tumor-specific T cells, we now know that there are distinct forms of inflammatory and immune responses that are procarcinogenic. Thus, two frontiers in cancer immunology are the elucidation of how the tumor organizes its immune microenvironment and the nature of immune responses that are anticarcinogenic versus procarcinogenic. As the receptors, ligands, and signaling pathways that mediate immune tolerance and immune-induced procarcinogenic events are elucidated, these factors and pathways can be selectively inhibited by both antibodies and drugs in a way to shift the balance to antitumor immune responses. This chapter outlines the major features of tumor–immune system interactions and set the stage for molecularly based approaches to manipulate immune responses for successful cancer therapy. The clinical results over the past few years, particularly with checkpoint blockade, validate clinically the tremendous potential of the immune system to destroy cancer cells (Figure 52-1 ).