Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression

Abstract

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-B, 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. (Cancer Res 2006; 66(11): 5527-36)

Pulmonary Mycobacterial Granuloma

“…Specifically, many tumors as well rely on the induction of IL-10 and other immune suppressive cytokines to dampen type 1 immune responses and to remain immune evasive. 65 In a fashion similar to that of the tumor, although it is believed that mycobacteria may simultaneously use multiple mechanisms of immune evasion including mechanisms of down-regulating antigen presentation, 42,61 in the current study we have shown that IL-10 is one of the essential mechanisms through which the immune suppressive environment of mycobacterial granuloma is maintained. Despite the overwhelming evidence to support a direct role of mycobacterial infection in inducing IL-10 production by APCs, [37][38][39]62 it is plausible for us to consider the possibility that some level of IL-10 may be actively induced as part of host immune regulatory mechanisms as a means to limit immunopathology, a concession that could be exploited by mycobacteria and has recently been suggested by others.…”

Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins

“…The activation status of tumor-associated macrophages may also be critical, with Stat-1 expression, essential for IFNγ signaling, an apparently adverse prognostic factor (14). Although prognosis is complicated by combining pathogenesis with response to therapy, these findings place FL-associated macrophages in line with other tumor-associated macrophages that have been shown to promote tumor progression (15) by multiple pathways, possibly including suppression of immune responses (16).…”

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

“…Success of mAb therapies in the clinic is limited by several underlying mechanisms including underappreciated TME-mediated host immune response suppression, such as reduced malignant cell killing by CD8 þ CTLs and/or NK cells, and properties of some immune cells harboring protumor activities (25). In addition, tumor cells have been shown to use multiple immunosuppressive mechanisms to avoid host immune attack, including tumor-induced impairment of antigen presentation (41,42), secretion of immunosuppressive and growth factors (e.g., TGFb and IL10) in the TME (43,44), amplification of receptor tyrosine kinases (45), upregulation/expression of negative costimulatory signaling molecules (CTLA-4 binding CD80 and/or CD86, PD-L1 and/or PD-L2) by tumor cells (46,47), inhibition of dendritic cell differentiation and maturation (44,46), and increased infiltration of regulatory T-cells (48,49). Here, we demonstrate that an HA high tumor ECM enables formation of a protective pericellular matrix coat capable of inhibiting access of NK cells to tumor cells in vitro as well as antibody and NK cell access in vivo, suggesting a novel mechanism for cancer cells to escape detection and clearance by antibody-and NK cell-mediated ADCC.…”