Ad.Egr-TNF and local ionizing radiation suppress metastases by interferon-beta-dependent activation of antigen-specific CD8+ T cells.
Ad.Egr-TNF is a radioinducible adenovector currently in phase 3 trials for inoperable pancreatic cancer. The combination of Ad.Egr-TNF and ionizing radiation (IR) contributes to local tumor control through the production of tumor necrosis factor-alpha (TNFalpha) in the tumor microenvironment. Moreover, clinical and preclinical studies with Ad.Egr-TNF/IR have suggested that this local approach suppresses the growth of distant metastatic disease; however, the mechanisms responsible for this effect remain unclear. These studies have been performed in wild-type (WT) and TNFR1,2(-/-) mice to assess the role of TNFalpha-induced signaling in the suppression of draining lymph node (DLN) metastases. The results demonstrate that production of TNFalpha in the tumor microenvironment induces expression of interferon (IFNbeta). In turn, IFNbeta stimulates the production of chemokines that recruit CD8(+) T cells to the tumor. The results further demonstrate that activation of tumor antigen-specific CD8(+) CTLs contributes to local antitumor activity and suppression of DLN metastases. These findings support a model in which treatment of tumors with Ad.Egr-TNF and IR is mediated by local and distant immune-mediated antitumor effects that suppress the development of metastases.
Meng
Yuru
Y
Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois, USA.
Mauceri
Helena J
HJ
Khodarev
Nikolai N
NN
Darga
Thomas E
TE
Pitroda
Sean P
SP
Beckett
Michael A
MA
Kufe
Donald W
DW
Weichselbaum
Ralph R
RR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D049109:Cell Proliferation; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009362:Neoplasm Metastasis / Q000235:genetics / Q000517:prevention & control* / Q000628:therapy*; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta