Extrinsic Cellular Suppression of Anti Tumor Immunity

Several cell populations have been described in tumor-bearing patients and animals that suppress anti-tumor immunity.

• Tumor-associated macrophages may promote tumor growth and invasiveness by altering the tissue microenvironment and by suppressing T cell responses. These macrophages have an M2 phenotype, as we discussed briefly earlier in the chapter, and they secrete mediators, such as IL-10, prostaglandin E2, and arginase, that impair T cell activation and effector functions. Tumor-associated macrophages also secrete factors that promote angiogenesis, such as TGF-P and VEGF, which enhances tumor growth.

• Regulatory T cells may suppress T cell responses to tumors. Evidence from mouse model systems and cancer patients indicates that the numbers of regulatory T cells are increased in tumor-bearing individuals, and these cells can be found in the cellular infiltrates in certain tumors. Depletion of regulatory T cells in tumor-bearing mice enhances anti-tumor immunity and reduces tumor growth.

• Myeloid-derived suppressor cells (MDSCs) are immature myeloid precursors that are recruited from the bone marrow and accumulate in lymphoid tissues, blood, or tumors of tumor-bearing animals and cancer patients and suppress anti-tumor innate and T cell responses. MDSCs are a heterogeneous group of cell types, including precursors of dendritic cells, mono-cytes, and neutrophils. They share some common surface markers, including Ly6C or Ly6G and CD11b in mice and CD33, CD11b, and CD15 in humans. Recruitment of MDSCs from the bone marrow into lymph nodes and other tissues is induced by various proinflammatory mediators produced by tumors. These mediators, which include prostaglandin E2, IL-6, VEGF, and complement fragment C5a, are not specific to tumors, and in fact, MDSCs accumulate at sites of chronic inflammation unrelated to tumors. MDSCs suppress innate immune responses by secreting IL-10, which inhibits various macrophage inflammatory functions. MDSCs suppress T cell responses by a variety of mechanisms. They express arginase and inducible nitric oxide synthase, which work together in generating reactive oxygen species, such as per-oxynitrite, that inhibit T cell activation. MDSCs also produce indolamine 2,3-dioxygenase, which catabo-lizes tryptophan needed for T cell proliferation. MDSCs indirectly impair anti-tumor T cell responses by inducing the development of regulatory T lymphocytes (Tregs) and skewing helper T cell differentiation toward TH2 cells.

Other host cells and mechanisms that may inhibit anti-tumor immunity are described later.

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