Tumors evolve mechanisms to escape immune control by a process called immune editing, which provides a selective pressure in the tumor microenvironment that could lead to malignant progression. A variety of
tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including
vascular endothelial growth factor,
interleukin-10,
transforming growth factor-beta,
prostaglandin E(2), and soluble
phosphatidylserine, soluble Fas, soluble
Fas ligand, and soluble
MHC class I-related chain A proteins. Although deposited at the primary
tumor site, these secreted factors could extend immunosuppressive effects into the local lymph nodes and the spleen, promoting invasion and
metastasis.
Vascular endothelial growth factors play a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as
tumor-associated immature dendritic cells and tumor-associated macrophages. The understanding of the immunosuppressive networks that evolve is incomplete, but several features are emerging. Accumulation of
tumor-associated immature dendritic cells may cause roving dendritic cells and T cells to become suppressed by the activation of
indoleamine 2,3-dioxygenase and
arginase I by
tumor-derived
growth factors. Soluble
phosphatidylserines support tumor-associated macrophages by stimulating the release of anti-inflammatory mediators that block antitumor immune responses. Soluble Fas, soluble FasL, and soluble
MHC class I-related chain A proteins may help
tumor cells escape cytolysis by cytotoxic T cells and natural killer cells, possibly by counterattacking immune cells and causing their death. In summary,
tumor-derived factors drive the evolution of an immunosuppressive network which ultimately extends immune evasion from the primary
tumor site to peripheral sites in patients with
cancer.