FASL –844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer

Abstract

The FAS receptor–ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis. We have recently demonstrated (Sun, T., X. Miao, X. Zhang, W. Tan, P. Xiong, and D. Lin. 2004. J. Natl. Cancer Inst. 96:1030–1036; Zhang, X., X. Miao, T. Sun, W. Tan, S. Qu, P. Xiong, Y. Zhou, and D. Lin. 2005. J. Med. Genet. 42:479–484) that functional polymorphisms in FAS and FAS ligand (FASL) are associated with susceptibility to lung cancer and esophageal cancer; however, the mechanisms underlying this association have not been elucidated. We show that the FAS –1377G, FAS –670A, and FASL –844T variants are expressed more highly on ex vivo–stimulated T cells than the FAS –1377A, FAS –670G, and FASL –844C variants. Moreover, activation-induced cell death (AICD) of T cells carrying the FASL –844C allele was increased. We also found a threefold increased risk of cervical cancer among subjects with the FASL –844CC genotype compared with those with the –844TT genotype in a case-control study in Chinese women. Together, these observations suggest that genetic polymorphisms in the FAS–FASL pathway confer host susceptibility to cervical cancers, which might be caused by immune escape of tumor cells because of enhanced AICD of tumor-specific T cells.

Immunization with autologous T cells enhances in vivo anti-tumor immune responses accompanied by up-regulation of GADD45β

“…There are many factors involved in the AICD. Fas and FasL are very important proteins in the AICD process [36,37]. Fas is a molecule expressed on activated T cells and serves as an activation marker for T cells.…”

“…This means that immunization induced Fas expression in T cells, but that the FasL transcription was not upregulated simultaneously. It is well known that high Fas with low FasL will keep the activated T cells resistant to AICD [37,38].…”

A Polymorphic −844T/C in FasL Promoter Predicts Survival and Relapse in Non–Small Cell Lung Cancer

“…Peripheral blood mononuclear cells (PBMC) from healthy donors were isolated by Ficoll-Paque (GE Healthcare) density-gradient centrifugation as described previously (21). The PBMCs were used for the determination of cancer cell-induced T-cell apoptosis by coculture with lung cancer cells (TL4, A427, H1355, and TL13) at a ratio of 10:1 for 36 hours.…”

“…A series of case-controlled studies from Lin's group indicated that the functional FasL À844T/C polymorphism in a Chinese population was associated with an increased risk of different human cancers, including those of the cervix, lung, esophagus, breast, and pancreas (18)(19)(20)(21)(22).…”

“…A higher prevalence of T-cell apoptosis in the FasL À844CC carrier was expected to cause a greater enhancement of tumor progression and metastasis via immune escape (19,21). In fact, the FasL protein was overexpressed in different tumors, including colon, breast, liver, gastric, ovary, and lung carcinomas (2,5,(23)(24)(25)(26)(27)(28)(29).…”