The microenvironments of some tumors also contain populations of myeloid cells, collectively called myeloid-derived suppressor cells (MDSCs), which can inhibit T-cell activation within the tumor. MDSCs may be heterogeneous, comprising both monocytic and polymorphonuclear cells, and are incompletely characterized at present. Several tumors of different tissue origins, such as melanoma, ovarian carcinoma, and B-cell lymphoma, have also been shown to produce the immunosuppressive cytokine IL-10, which can reduce dendritic cell activity and inhibit T-cell activation.
Some tumors express cell-surface proteins that directly inhibit immune responses (see Fig. 16.14, fourth panel). For example, some tumors express programmed death ligand-1 (PD-L1), a B7 family member and ligand for the inhibitory receptor PD-1 expressed by activated T cells (see Section 7-24). Furthermore, tumors can produce enzymes that act to suppress local immune responses. The enzyme indoleamine 2,3-dioxygenase (IDO) catabolizes tryptophan, an essential amino acid, in order to produce the immunosuppressive metabolite kynurenine. IDO seems to function in maintaining a balance between immune responses and tolerance during infections, but can be induced during the equilibrium phase of tumor development. Finally, tumor cells can produce materials such as collagen that create a physical barrier to interaction with cells of the immune system (see Fig. 16.14, last panel).
Fig. 16.15 Loss of MHC class I expression in a prostatic carcinoma.
Some tumors can evade immune surveillance by a loss of expression of MHC class I molecules, preventing their recognition by CD8 T cells. Shown is a section of a human prostate cancer that has been stained with a peroxidase-conjugated antibody against HLA class I molecules. The brown stain that represents HLA class I expression is restricted to infiltrating lymphocytes and tissue stromal cells. The tumor cells that occupy most of the section show no staining. Photograph courtesy of G. Stamp.
Fig. 16.16 Tumors that lose expression of all MHC class I molecules as a mechanism of escape from immune surveillance are more susceptible to being killed by NK cells. Regression of transplanted tumors is largely due to the actions of cytotoxic T lymphocytes (CTLs), which recognize novel peptides bound to MHC class I antigens on the surface of the cell (left panels). NK cells have inhibitory receptors that bind MHC class I molecules, so variants of the tumor that have low levels of MHC class I, although less sensitive to CD8 cytotoxic T cells, become susceptible to NK cells (center panels). Although nude mice lack T cells, they have higher than normal levels of NK cells, and so tumors that are sensitive to NK cells grow less well in nude mice than in normal mice. Transfection with MHC class I genes can restore both resistance to NK cells and susceptibility to CD8 cytotoxic T cells (right panels). The bottom panels show scanning electron micrographs of NK cells attacking leukemia cells. The NK cell is the smaller cell on the left in both photographs. Left panel: shortly after binding to the target cell, the NK cell has put out numerous microvillous extensions and established a broad zone of contact with the leukemia cell. Right panel: 60 minutes after mixing, long microvillous processes can be seen extending from the NK cell (bottom left) to the leukemia cell and there is extensive damage to the leukemia cell; the plasma membrane has rolled up and fragmented. Photographs reprinted from Herberman, R., and Callewaert, D: Mechanisms of Cytotoxicity by Natural Killer Cells, 1985, with permission from Elsevier.
16-15 Tumor rejection antigens can be recognized by T cells and form the basis of immunotherapies.