Immune Mechanisms of Tumor Rejection
المؤلف:
Abbas, A. K., Lichtman, A. H., & Pillai, S
المصدر:
Basic Immunology : Function and disorders of immune system
الجزء والصفحة:
6th ed , page199-200
2025-05-21
412
The principal immune mechanism of tumor eradication is killing of tumor cells by CTLs specific for tumor antigens. The majority of tumor neoantigens that elicit immune responses in tumor-bearing individuals are endogenously synthesized cytosolic or nuclear proteins that are processed by proteasomes and displayed as class I MHC–associated peptides. Therefore, these antigens are recognized by class I MHC–restricted CD8+ CTLs, whose function is to kill cells producing the antigens. The role of CTLs in tumor rejection has been established in animal models: tumors can be destroyed by transferring tumor-reactive CD8+ T cells into the tumor-bearing animals. Studies of many human tumors indicate that abundant CTL infiltration predicts a more favorable clinical course compared with tumors with sparse CTLs.
CTL responses against tumors are initiated by recognition of tumor antigens on host antigen-presenting cells (APCs). The APCs ingest tumor cells or their antigens and present the antigens to naive CD8+ T cells in draining lymph nodes (Fig. 1). Tumors may arise from virtually any nucleated cell type in any tissue, and, like all nucleated cells, they usually express class I MHC molecules, but often they do not express costimulators or class II MHC molecules. We know, however, that the activation of naive CD8+ T cells to proliferate and differentiate into active CTLs requires recognition of antigen (class I MHC–associated peptide) on dendritic cells in secondary lymphoid organs and also costimulation and/or help from class II MHC restricted CD4+ T cells . How, then, can tumors of different cell types stimulate CTL responses? The likely answer is that tumor cells or their proteins are ingested by the host’s dendritic cells, transported to lymph nodes draining the site of the tumor, and the protein anti gens of the tumor cells are processed and displayed by class I MHC molecules on the host dendritic cells. This process, called cross-presentation or cross-priming. Dendritic cells can also present peptides derived from ingested tumor anti gens on class II MHC molecules. Thus, tumor antigens may be recognized by CD8+ T cells and by CD4+ T cells.
Fig1. Immune response against tumors. Tumor antigens are picked up by host dendritic cells and responses are initiated in peripheral (secondary) lymphoid organs. Tumor-specific CTLs migrate back to the tumor and kill tumor cells. Other mechanisms of tumor immunity are not shown. CTL, Cytotoxic T lymphocyte.
At the same time that dendritic cells are presenting tumor antigens, they may express costimulators that provide signals for the activation of the T cells. It is not known how tumors induce the expression of costimulators on APCs because, as discussed in Chapter 5, the physiologic stimuli for the induction of costimulators are usually microbes, and tumors are generally sterile. A likely possibility is that tumor cells die if their growth outstrips their blood and nutrient supply, and adjacent normal tissue cells may be injured and die due to the invasive tumor. These dying cells release products (dam age-associated molecular patterns; that stimulate innate responses. The activation of APCs to express costimulators is part of these responses.
Once naive CD8+ T cells have differentiated into effector CTLs, they are able to migrate back to any site where the tumor is growing, and kill tumor cells expressing the relevant antigens without a requirement for costimulation or T cell help.
Immune mechanisms in addition to CTLs may play a role in tumor rejection. Antitumor CD4+ T cell responses have been detected in patients, and increased numbers of CD4+ effector T cells, especially Th1 cells, in tumor infiltrates are associated with good prognosis. Antitumor antibodies are also detectable in some cancer patients, but whether these antibodies protect individuals against tumor growth has not been established. Experimental studies have shown that activated macrophages and natural killer (NK) cells are capable of killing tumor cells, and T h1 responses work largely by activating macrophages, but the protective role of these effector mechanisms in tumor-bearing patients is not clearly established.
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