Lymphotoxin induces tumor evasion through TGF-beta signaling (100.10)

Abstract

Abstract While major histocompatibility class I (MHC class I) expression was inhibited in mice administrated with pIRES-LTab plasmid, it was elevated in the spleen and liver of lymphotoxin(LT)a-/- and LTbR-/- mice. Consistent with this, the expression of genes that upregulated MHC class I was downregulated in mice administrated with pIRES-LTab plasmid, but it was upregulated in the spleen and liver of LTa-/- and LTbR-/- mice. In addition, gene expression of Fas and FasL was also regulated by LT in vitro and in vivo. Whereas gene expression of TGF-b receptor was upregulated in the large intestine of LTa-/- and LTbR-/- mice, its expression was increased in mice immunized with pIRES-LTab plasmid as a DNA adjuvant. Administration of pIRES-LTab plasmid prolonged the survival rate of mice challenged with human papillomavirus (HPV)-transformed mouse TC-1 tumor cells, and delayed the growth rate of the TC-1 cells. Gene expression of smad3 and smad4 was increased in colon and small intestine of LTa-/- and LTbR-/- mice. These results collectively suggested that MHC class I expression was regulated by LT-induced upregulation of TGF-b expression, and subsequently tumor evasion might be induced by suppression of MHC class I.