The Fas/Fas Ligand Pathway Is Important for Optimal Tumor Regression in a Mouse Model of CTL Adoptive Immunotherapy of Experimental CMS4 Lung Metastases

Abstract

The mechanisms of CTL-mediated tumor regression in vivo remain to be fully understood. If CTL do mediate tumor regression in vivo by direct cytotoxicity, this may occur via two major effector mechanisms involving the secretion of perforin/granzymes and/or engagement of Fas by Fas ligand (FasL) expressed by the activated CTL. Although the perforin pathway has been considered the dominant player, it is unclear whether Fas-mediated cytotoxicity is additionally required for optimal tumor rejection. Previously, we produced H-2Ld-restricted CTL reactive against the CMS4 sarcoma, which expresses a naturally occurring rejection Ag recognized by these CTL and harbors a cytokine (IFN-γ plus TNF)-inducible, Fas-responsive phenotype. The adoptive transfer of these CTL to syngeneic BALB/c mice with minimal (day 3 established) or extensive (day 10 established) experimental pulmonary metastases resulted in strong antitumor responses. Here we investigated whether a FasL-dependent CTL effector mechanism was important for optimal tumor regression in this adoptive immunotherapy model. The approach taken was to compare the therapeutic efficacy of wild-type to FasL-deficient (gld) CTL clones by adoptive transfer. In comparison with wild-type CTL, gld-CTL efficiently mediated tumor cytolysis and produced comparable amounts of IFN-γ, after tumor-specific stimulation, as in vitro assessments of Ag recognition. Moreover, gld-CTL mediated comparably potent antitumor effects in a minimal disease setting, but were significantly less effective under conditions of an extensive tumor burden. Overall, under conditions of extensive lung metastases, these data revealed for the first time an important role for a FasL-dependent CTL effector mechanism in optimal tumor regression.

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

“…Thus, reduced sensitivity to CD95-mediated apoptosis signals can conceivably lead to escape of virusinfected cells from immune surveillance. [17][18][19][20][21][22] Here we have found elevated levels of HGF and EGF in HBVinfected individuals and show that these growth factors stimulate survival signaling in primary human hepatocytes. Our findings support the notion that survival programs induced by EGF/HGF signaling may contribute to an apoptosis resistant phenotype in hepatocytes in the infected liver, thus contributing to immune escape and persistence of the viral infection.…”

Solid tumors “melt” from the inside after successful CD8 T cell attack

“…Perforin-deficient mice were reported to be more susceptible to tumor development in some models [5][6][7][8], while other studies found that perforin-deficient CTL were fully capable of exerting anti-tumor activity in vivo [9][10][11][12][13]. Similarly, CD95L-dependent effector mechanisms have been shown to be important in some models [14][15][16] but not in others [9,13,17]. The release of soluble factors represents an additional mechanism by which CD8 T cells could exert anti-tumor activity.…”

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

“…In the presence of extensive lung metastases, Fas/FasL signaling plays an important role in CTL-prompted tumor regression. 3 However, in CTL-based immunotherapy, tumor cells are unresponsive to tumor infiltrating lymphocytes (TILs) and thus, the susceptibility of tumor cells to Fasmediated cytotoxicity is diminished, ultimately leading to tumor escape. Our previous work showed that exosomes derived from activated T cells promoted tumor invasion via the Fas signaling pathway.…”