Tumor-specific T cells signal tumor destruction via the lymphotoxin beta receptor

Tumor-specific T cells signal tumor destruction via the lymphotoxin beta receptor

Beschreibung

vor 17 Jahren
Background: Previously, we reported that adoptively transferred
perforin k/o (PKO), and IFN-gamma\k/o (GKO), or perforin/IFN-gamma
double k/o (PKO/GKO) effector T cells mediated regression of
B16BL6-D5 (D5) pulmonary metastases and showed that TNF receptor
signaling played a critical role in mediating tumor regression. In
this report we investigated the role of lymphotoxin-alpha
(LT-alpha) as a potential effector molecules of tumor-specific
effector T cells. Methods: Effector T cells were generated from
tumor vaccine-draining lymph node (TVDLN) of wt, GKO, LT-alpha
deficient (LKO), or PKO/GKO mice and tested for their ability to
mediate regression of D5 pulmonary metastases in the presence or
absence of LT-beta R-Fc fusion protein or anti-IFN-gamma antibody.
Chemokine production by D5 tumor cells was determined by ELISA,
RT-PCR and Chemotaxis assays. Results: Stimulated effector T cells
from wt, GKO, or PKO/GKO mice expressed ligands for LT-beta
receptor (LT-beta R). D5 tumor cells were found to constitutively
express the LT-beta R. Administration of LT-beta R-Fc fusion
protein completely abrogated the therapeutic efficacy of GKO or
PKO/GKO but not wt effector T cells (p < 0.05). Consistent with
this observation, therapeutic efficacy of effector T cells
deficient in LT-alpha, was greatly reduced when IFN-gamma
production was neutralized. While recombinant LT-alpha 1 beta 2 did
not induce apoptosis of D5 tumor cells in vitro, it induced
secretion of chemokines by D5 that promoted migration of
macrophages. Conclusion: The contribution of LT-alpha expression by
effector T cells to anti-tumor activity in vivo was not discernable
when wt effector T cells were studied. However, the contribution of
LT-beta R signaling was identified for GKO or PKO/GKO effector T
cells. Since LT-alpha does not directly induce killing of D5 tumor
cells in vitro, but does stimulate D5 tumor cells to secrete
chemokines, these data suggest a model where LT-alpha expression by
tumor-specific effector T cells interacts via cross-linking of the
LT-beta R on tumor cells to induce secretion of chemokines that are
chemotactic for macrophages. While the contribution of macrophages
to tumor elimination in our system requires additional study, this
model provides a possible explanation for the infiltration of inate
effector cells that is seen coincident with tumor regression.

Kommentare (0)

Lade Inhalte...

Abonnenten

15
15
:
: