Systemic and Local Suppression of T Cells

Immunosuppressive mechanisms that promote tumor growth include suppressive factors directly produced by tumor cells and those that are produced by other cells, although induced by the tumor. The most studied suppressive factor that can be produced by both the tumor and immunocompetent cells is the transforming growth factor-P (TGF-P). TGF-P inhibits differentiation of both CD4+ and CD8+ naive T cells via different transcriptional activators (16). Blocking of TGF-P signals in T cells in mice leads to the generation of potent CTL responses that results in tumor rejection (16). In addition to its direct effect on T-cell function, TGF-P also inhibits T cells indirectly through its effects on APCs (16). An increased concentration of TGF-P in serum of pancreatic cancer patients has been positively correlated with a loss of CD3 Z-chain in tumor-infiltrating lymphocytes (17). Other suppressive factors that impare T-cell function systemically (with an impact on proliferative responses to mitogens and cytokine production) include PGE2 (18), prostate-specific antigen (PSA) (19), and colon cancer mucin (20). These factors might significantly impare tumor-infiltrating lymphocyte function because of the expected increased concentrations of these factors in the tumor microenvironment.

Local immunosuppression could also be associated with the overexpression of metalloproteases (MMP)-1, MMP-2, and MMP-9 in cervical cancer tissues. This resulted in an intratumoral release of a cleaved IL-2 receptor (IL-2Ra) from the surface of tumor-infiltrating lymphocytes (21). Because of the critical role of IL-2Ra in the maintenance and expansion of CTLs in the tumor site, rapid cleavage of IL-2Ra by MMP-9 was suggested to be responsible for the downregulation of the proliferative capability of cancer-encountered T cells (21).

The indirect influence of tumors on the development of a systemic immunosuppresion can be attributed to hyperproduction of IL-10, oxygen metabolism intermediates, and some enzymes. IL-10 is a type 2 cytokine that is produced by APCs and Th2 cells. It is involved in the development of T-cell anergy, promotion of Th2 responses, and inhibition of Th1 responses, which are important for the generation of efficient antitumor responses. Increased production of oxygen metabolites by macrophages isolated from the metastatic lymph nodes of patients with malignant melanoma was found to be responsible for decreased CD3-mediated stimulation of T cells and the reduction of CTL and NK cell activity (22). The inhibitory effect of macrophages on melanoma-specific CTL lines and NK cells was abrogated in the presence of catalase, a scavenger for H2O2. The mechanism of H2O2-induced immunosuppression by monocytes/macrophages derived from the blood of cancer patients was attributed to the inhibition of Th1 cytokine production in memory/activated T cells, which correlated with the the blocking of NF-kB activation (23) and reduction of phosphorylation and activation of JAK3/STAT5 signal transduction proteins (24). Increased oxidative stress in cancer patients has been suggested as one of the mechanisms behind the tumor-induced immunosuppression, and dietary supplementation of antioxidative formulation that included vitamin E, vitamin C, and selenium significantly increased number of CD3-stimulated IFN-y-producing CD8+ CD45RO+ memory T cells in patients with advanced colorectal cancer (25). The increase in the number of phorbolmiristylacetate-ionomycin-activated T cells producing IL-2 following antioxidant therapy was statistically significant for all subsets of T cells (CD4+, CD8+, CD45RO-, CD45RO+) (25). Further, the short-course (for 2 wk) antioxidant therapy resulted in increased CD4:CD8 T-cell ratios. Whether the similar treatment would have an impact on the efficiency of vaccination against cancer, and whether other cancers would show similar results of antioxidative treatment remain to be elucidated.

Another mechanism that mediates both the direct and indirect immunosuppressive capability of tumor includes the overexpression of immunosuppressive, IFN-y-inducible enzyme, indolamine 2,3-dioxygenase (IDO), by mononuclear cells evading tumors and tumor-draining lymph nodes, and by tumors itself (26,27). This enzyme is responsible for the catabolism of tryptophan (the amino acid that is critical for T-cell function), and a competitive inhibitor of IDO, 1-methyl-tryptophan (1-MT), can prevent the interference of APCs with T-cell function (27,28). Recent studies demonstrated that murine IDO-negative Lewis lung carcinoma recruited IDO-positive mononuclear cells in the tumor site and draining lymph nodes. Sustained delivery of 1-MT inhibited IDO and significantly delayed carcinoma cell growth in syngeneic mice and improved T-cell activity in the presence of carcinoma cells (29). These data provide the first evidence that IDO can contribute to tumor-induced immunosuppression. Interestingly, human monocyte-

derived DCs upon activation with CD40 ligand and IFN-y or in the presence of activated T cells produce IDO that results in the inhibition of T-cell proliferation (28). Whether the overexpression of IDO in some tumors has an impact on T-cell function, and whether macrophages/monocytes and/or DCs in cancer patients overexpress IDO in the tumor site and significantly contribute to the suppression of tumor infiltrating lymphocyte function, are critical issues for future studies.

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