Downregulation of IFN‐γR in association with loss of Fas function is linked to tumor progression

Abstract

The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells, and it has been demonstrated that lymphocytes and IFN-c are the primary tumor suppressors of the immune system. However, the immune system can concurrently select for tumor variants with reduced immunogenicity and aggressive phenotypes. We report here that tumor escape variants that have survived CTL adoptive immunotherapy exhibited decreased expression levels of both Fas and IFN-cR in vitro. Furthermore, examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed that both Fas and IFN-cR protein levels were dramatically lower in lung metastases than in primary tumors in vivo. Functional disruption of either the Fas-or the IFN-c signaling pathway enhanced the colonization efficiency of preexisting metastatic tumor cells, whereas disruption of both Fas and IFN-cR pathways resulted in synergistic augmentation of the colonization efficiency of the preexisting metastatic tumor cells, as determined by experimental lung metastases assay. Gene expression profiling revealed that altered expression of genes involved in immediate IFN-cR signaling, the interferon primary response, apoptosis and tumor colonization is associated with loss of IFN-cR function and enhanced metastatic potential. Interestingly, disruption of IFN-cR function did not alter tumor cell susceptibility to CTL-mediated cytotoxicity, but is linked to enhanced infiltration of endogenous T cells in the tumor microenvironment in vivo. These findings suggest that coordinate downregulation of Fas and IFN-cR, 2 key components of cancer immunosurveillance system on tumor cells, leads to a more aggressive metastatic phenotype. ' 2007 Wiley-Liss, Inc.

Loss of Fas expression and high expression of HLA-E promoting the immune escape of early colorectal cancer cells

“…Previous studies have demonstrated that Fas is highly expressed in normal colorectal epithelial cells, whilst a loss of Fas expression and anti-Fas-mediated apoptosis in colorectal cancer cells contributed to tumor invasion and metastasis (6,7,19). The present study indicated that the expression of Fas reduced significantly as the malignancy of the epithelial cells increased (P=0.0271).…”

Smad7 Expression in T cells Prevents Colitis-Associated Cancer

“…IFNg expression is also essential for CD8-mediated antitumor activity. This effect can be partially explained by the capacity of IFNg to induce Fas on dysplastic target cells surface thus inducing cell death by Fas ligand-Fas interaction (35,36). Moreover, IFNg increases the expression of MHC class I expression on target cells thus promoting recognition of tumor-associated antigens (37).…”

Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity

“…Mice lacking sensitivity to IFNg, such as IFNg receptor-deficient mice, developed tumors more rapidly and with greater frequency than IFNg-sensitive mice (25). Tumor escape variants that survive CTL adoptive immunotherapy exhibit decreased expression levels of the IFNg receptor (26). In humans, IFNg receptor a expression is lower in cases of infiltrating breast cancer than in cases of in situ tumors (27).…”