Targeting the effector site with IFN-alphabeta-inducing TLR ligands reactivates tumor-resident CD8 T cell responses to eradicate established solid tumors.
Effective antitumor CD8 T cell responses may be activated by directly targeting the innate immune system within tumors. We investigated this response by injecting a range of TLR agonists into established tumors using a mouse model of malignant mesothelioma stably transduced with the hemagglutinin (HA) gene as a marker Ag (AB1-HA). Persistent delivery of the dsRNA mimetic poly(I:C) into established AB1-HA tumors resulted in complete tumor resolution in 40% of mice, with the remaining mice also showing a significant delay in tumor progression. Experiments in athymic nude mice along with CD8 depletion and IFN-alphabeta blocking studies revealed that tumor resolution required both CD8 T cells and type I IFN induction, and was associated with local changes in MHC class I expression. Surprisingly, however, tumor resolution was not associated with systemic dissemination or tumor infiltration of effector CD8 T cells. Instead, the antitumor response was critically dependent on the reactivation of tumor-resident CD8 T cell responses. These studies suggest that, once reactivated, pre-existing local CD8 T cell responses are sufficient to resolve established tumors and that in situ type I IFN is a determining factor.
Currie
Andrew J
AJ
National Research Centre for Asbestos Related Diseases, QEII Medical Centre, Verdun Street, Nedlands, Perth 6009, Western Australia. ajcurrie@cyllene.uwa.edu.au
van der Most
Robbert G
RG
Broomfield
Steve A
SA
Prosser
Amy C
AC
Tovey
Michael G
MG
Robinson
Bruce W S
BW
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D016898:Interferon-alpha / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D008024:Ligands; D008212:Lymphocyte Depletion; D008654:Mesothelioma / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009696:Nucleic Acids / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology
D000998:Antiviral Agents; D016898:Interferon-alpha; D008024:Ligands; D009696:Nucleic Acids; D012330:RNA, Double-Stranded; D016899:Interferon-beta; D011070:Poly I-C