Tumor escape mechanisms. The immune system exerts selective pressure on tumors through a variety of processes, including the destruction of antigen-positive tumor cells by CD8 + T cells. As a result, immunogenic tumor cells are eliminated, leaving behind tumor cell variants more adept at evading immune-mediated destruction (i.e., immunoselection). Over time, tumors evolve mechanisms to elude or inhibit immunity by both intrinsic and extrinsic means. Intrinsic alterations within tumor cells evade immunity by downregulating antigen presentation (MHC), upregulating inhibitors of apoptosis (Bcl- XL, FLIP), or expressing inhibitory cell surface molecules that directly kill cytotoxic T cells (PD-L1, FasL). In addition, tumor cells secrete factors that inhibit effector immune cell functions (TGF-β, IL-10, VEGF, LXR-L, IDO, gangliosides, or soluble MICA) or recruit regulatory cells to generate an immunosuppressive microenvironment (IL-4, IL-13, GM-CSF, IL-1β, VEGF, or PGE2). Once recruited, regulatory cells attenuate antitumor immunity through the liberation of immunosuppressive cytokines and alterations in the nutrient content of the microenvironment. Specifically, secretion of IL-4 and IL-13 leads to recruitment and polarization of M2 macrophages (M2 MΦ) from myeloid precursors, which express TGF-β, IL-10, and PDGF that inhibit T cells. The release of colony-stimulating factors, IL-1β, VEGF, or PGE2 by tumor cells results in the accumulation of MDSCs that can block T cell function by expressing TGF-β, ARG1, and iNOS. Regulatory T cells (Tregs) can also inhibit effector T cells through multiple mechanisms, including expression of CTLA-4. (Abbreviations: ARG1, arginase 1; Bcl-XL, B cell lymphoma extra-long; CTLA-4, cytotoxic T lymphocyte associated protein-4; DC, dendritic cell; FasL, Fas ligand; FLIP, apoptosis-stimulating fragment-associated protein with death domain-like interleukin-1 converting enzyme-like inhibitory protein; GM-CSF, granulocyte macrophage colony–stimulating factor; IDO, indoleamine 2,3-deoxygenase; IL, interleukin; iNOS, inducible nitric oxide synthase; LXR-L, liver X receptor ligand; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; MICA, MHC class I polypeptide-related sequence A; PDGF, platelet-derived growth factor; PD-L1, programmed cell death 1 ligand 1; PGE2, prostaglandin-E2; TGF-β, transforming growth factor-β; Treg, regulatory T cell; VEGF, vascular endothelial growth factor) (Vesely et al. 2011).