Soluble factors released by activated cytotoxic T lymphocytes interfere with death receptor pathways in neuroblastoma

Abstract

Neuroblastoma (NB) is often described as an unfavorable target for both HLA-restricted and death receptor-mediated elimination by cytotoxic T lymphocytes (CTLs) due to low or absent HLA class I and caspase-8 expression. We investigated the effects of soluble factors released by CTLs activated by TCR triggering (named as activated supernatant; AS) on the levels and composition of cell surface molecules involved in HLA-restricted and HLA-independent NB cell recognition (surface immune phenotype). Using a panel of long-term propagated NB cell lines and freshly isolated primary human NB cells, we analyzed surface expression of the (1) cognate receptors for TNFalpha, Fas and TRAIL; (2) HLA class I and II heterodimers; (3) adhesion molecules; (4) the intracellular expression and activation of caspase-8, as well as (5) the susceptibility of NB cells to death receptor-mediated killing prior to and after exposure to AS. The exposure of NB cells to soluble factors released by activated CTLs skewed the surface immune phenotype of both long term cultured and primary NB cells, induced the expression and activation of caspase-8 and increased the susceptibility of tumor cells to lysis by TRAIL and Fas-agonistic antibody. Blocking experiments identified IFNgamma and TNFalpha as main factors responsible for modulating the surface antigens of NB cells by AS. Our data suggest that recruitment of CTLs activated on third party targets into the vicinity of the NB tumor mass, may override the "silent" immune phenotype of NB cells via the action of soluble factors.

Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors

“…ImmTAC-activated T cells release soluble factors including interferon-γ, IL-2 and TNFα (Fig. 1b), which can not only attract additional T cells and other effector immune cells to the tumor site but also promote components of the death receptor pathway in the tumor cells [52], which can result in long-term anti-tumor activity. In cancer patients, it is probable that mechanisms such as epitope spreading (activation of endogenous T cells specific for other tumor epitopes) will occur, following cross-presentation of antigens from lysed tumor cells by dendritic cells.…”

The microenvironment of human neuroblastoma supports the activation of tumor-associated T lymphocytes

“…Moreover, activated T cells can kill NB cells in an MHC-unrestricted fashion. We have previously shown that (1) activated cytotoxic T lymphocytes (CTLs) can induce the MHC-independent demise of NB cells not only in a caspase-dependent but also in a caspase-independent manner 4 and that (2) soluble factors released by activated CTLs sensitize NB cells to death receptor-mediated killing by T cells 5 . The latter observation is of special importance since the epigenetic silencing of caspase-8 has frequently been observed in NB cells (reviewed in ref.…”

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

“…ImmTAC-NYE was able to bind to cells with a lowdensity of HLA-A2/peptide complexes, suggesting maintained functionality despite MHC down-regulation. The study also found that ImmTAC-NYE-activated T cells release cytokines IFN-γ, IL-2, and TNF-α, which, in addition to attracting effector immune cells to the tumor site, may spur long-term anti-tumor activity by promoting components of the death receptor pathway in tumor cells, providing an additional mechanism of tumor cell killing even after the BsAb is metabolized (89,216).…”