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Table 4 Known or possible obstacles to immunologic control of tumor progression, which impact on both active immunotherapy (cancer vaccines) and adoptive immunotherapy.

From: Progress and controversies in developing cancer vaccines

1) Expression of tumor antigens in the absence of costimulatory molecules on tumor cells, leading to tolerance
2) Chronic antigen exposure, leading to upregulation of immuno-regulatory mechanisms
   a) CTLA4 expression
   b) Accumulation of regulatory T cells in the tumor microenvironment
3) Downregulation of MHC molecule expression by tumor cells
4) Downregulation of tumor antigen expression by tumor cells
5) Secretion of anti-inflammatory cytokines by tumor cells or tumor-associated stroma
   a) IL-10
   b) TGF-β
   c) Others
6) Expression of enzymes in the tumor microenvironment that interfere with T cell function
   a) Arginase
   b) Indoleamine 2,3-dioxygenase (IDO)
7) Propogation of a tumor microenvironment that is hostile to T cell activation
   a) Immunoregulatory function of dendritic cells
   b) Anergic tumor-infiltrating lymphocytes
8) Tumor-associated VEGF and other neovascularity-enhancing mechanisms may have immunoregulatory properties as well.
9) Homeostatic mechanisms in the host may limit expansion of tumor-specific T cell responses, and may limit expansion and persistence of tumor-specific T cell responses.
10) Resistance of tumor cells to apoptosis
11) Elaboration of compounds associated with tumor necrosis, that inhibit anti-tumor immunity locally