Effective Immune Responses to Tumor Antigens. Assuming that the immune system is normally capable of eliminating emerging cancers, we may ask, what are the key components of an effective host immune response? It appears likely that immune reactions to cancers are initiated by the death of individual cancer cells, which occurs at some frequency in all cancers due to dysregulated growth, metabolic stresses, and hypoxia due to insufficient blood supply. When tumor cells die they release “danger signals” (damage associated molecular patterns, see Chapter 5) that stimulate innate immune cells, including resident phagocytes and antigen presenting cells. It is believed that some of the dead cells are phagocytosed by dendritic cells, which migrate to draining lymph nodes and present tumor neoantigens in the context of MHC class I molecules, a process termed cross-presentation. The displayed tumor antigens are recognized by antigen-specific CD8+ T cells, which become activated, proliferate, differentiate into active CTLs, and home to the site of the tumor, where they recognize and kill tumor cells presenting neoantigens in the context of their own MHC class I molecules (
Fig. 6.29 ). IFN-γ-producing T helper cells of the Th1 subset, which may be induced by recognition of tumor antigens, can activate macrophages and also contribute to the destruction of tumors.
As will be discussed shortly, some the strongest evidence for the importance of CTL responses in immunosurveillance stems from the characterization of established human cancers, which often feature acquired mutations that prevent CTLs from recognizing tumor cells as “foreign”. It also has been noted in large studies of a wide variety of human tumors that high levels of infiltrating CTLs and Th1 cells correlate with better clinical outcomes. While other cell types such as natural killer cells also have been implicated in anti-tumor responses, the quality and strength of CTL responses are believed to be of preeminent importance.
Immune Evasion by Cancers. Since the immune system is capable of recognizing and eliminating nascent cancers, it follows that tumors that reach clinically significant sizes must be composed of cells that are either invisible to the host immune system or that express factors that actively suppress host immunity. The term cancer immunoediting has been used to describe the ability of the immune system to promote the darwinian selection of the tumor subclones that are most able to avoid host immunity or even manipulate the immune system for their own malignant purposes. Since CTL responses appear to be the most important defense that the host has against tumors, it should come as http://ebooksmedicine.net
CTL killing of tumor
Afferent Migration of lymphatictumor-specific vesselCTL to tumor
Activation of tumor antigen-specific CD8+ T cell
Fig. 6.29 Cross-presentation of tumor antigens and induction of CD8+ cytotoxic T cell antitumor response. (Modified from Abbas AK, Lichtman AH, Pillai S: Cellular and molecular immunology, ed 9, Philadelphia, 2018, Elsevier.) no surprise that tumor cells show a variety of alterations that abrogate CTL responses. These include acquired mutations in β2-microglobulin that prevent the assembly of functional MHC class I molecules, and increased expression of a variety of proteins that inhibit CTL function. These proteins work by activating what is referred to as immune checkpoints, inhibitory pathways that normally are crucial for maintaining self-tolerance and controlling the size and duration of immune responses so as to minimize collateral tissue damage.