Tumors can avoid stimulating an immune response or can evade it when it occurs by means of numerous mechanisms, which are summarized in Fig. 16.14. Spontaneous tumors may initially lack mutations that produce new tumor-specific antigens that elicit T-cell responses (see Fig. 16.14, first panel). And even when a tumor-specific antigen is expressed and is taken up and presented by antigen-presenting cells (APCs), if co-stimulatory signals are absent the antigen-presenting cell will tend to tolerize any antigen-specific naive T cells rather than activating them (see Fig. 16.14, second panel). How long such tumors are treated as ‘self’ is unclear. Recent sequencing of entire tumor genomes reveals that mutations may generate as many as 10–15 unique antigenic peptides that could be recognized as ‘foreign’ by T cells. In addition, cellular transformation is frequently associated with induction of MHC class Ib proteins (such as MIC-A and MIC-B) that are ligands for NKG2D, thus allowing tumor recognition by NK cells (see Section 6-17). But cancer cells tend to be genetically unstable, so that clones that are not recognized by an immune response may be able to escape elimination.
Some tumors, such as colon and cervical cancers, lose the expression of a particular MHC class I molecule, perhaps through immune selection by T cells specific for a peptide presented by that MHC class I molecule (see Fig. 16.14, third panel). In experimental studies, when a tumor loses expression of all MHC class I molecules (Fig. 16.15), it can no longer be recognized by cytotoxic T cells, although it might become susceptible to NK cells (Fig. 16.16). Tumors that lose only one MHC class I molecule might be able to avoid recognition by specific CD8 cytotoxic T cells while still remaining resistant to NK cells, conferring a selective advantage in vivo.
Tumors also seem to be able to evade immune attack by creating a micro-environment that is generally immunosuppressive (see Fig. 16.14, fourth panel). Many tumors make immunosuppressive cytokines. Transforming growth factor-β (TGF-β) was first identified in the culture supernatant of a
Fig. 16.14 Tumors can avoid immune recognition in a variety tumors may be eliminated. The genetic instability of tumors allows of ways. First panel: tumors can have low immunogenicity. Tumors antigenic change, part of an equilibrium phase, during which tumor may lack antigens recognized by T cells, may have lost one or more cells lacking immunogenic antigens can expand. Fourth panel: tumors MHC molecules, or may express inhibitory molecules such as PD-L1 often produce molecules, such as TGF-β, IL-10, IDO, or PD-L1, that that repress T-cell function. Second panel: tumor-specific antigens suppress immune responses directly or recruit regulatory T cells that may be cross-presented by dendritic cells without co-stimulatory can secrete immunosuppressive cytokines. Fifth panel: tumor cells signals, inducing a tolerant state in T cells. Third panel: tumors can can secrete molecules such as collagen that form a physical barrier initially express antigens to which the immune system responds. Such around the tumor, preventing lymphocyte access.
tumor (hence its name), and, as we have seen, it tends to suppress the inflammatory T-cell responses and cell-mediated immunity that are needed to control tumor growth. Recall that TGF-β induces the development of inducible regulatory T cells (Treg cells; see Section 9-21), which have been found in a variety of cancers and might expand specifically in response to tumor antigens. In mouse models, removal of Treg cells increases resistance to cancer, whereas their transfer into a Treg-negative recipient allows cancer cells to more greatly proliferate.