| RRC ID |
70296
|
| Author |
Temizoz B, Hioki K, Kobari S, Jounai N, Kusakabe T, Lee MSJ, Coban C, Kuroda E, Ishii KJ.
|
| Title |
Anti-tumor immunity by transcriptional synergy between TLR9 and STING activation.
|
| Journal |
Int Immunol
|
| Abstract |
Agonists for TLR9 and STING offer therapeutic applications both as anti-tumor agents and vaccine adjuvants, though their clinical applications are limited; the clinically available TLR9 agonist is a weak IFN inducer and STING agonists induce undesired type 2 immunity. The combinatorial use of TLR9- and STING-agonists overcome these limitations; in turn, synergized the induction of innate and adaptive IFNγ and became an advantageous type 1 adjuvant, suppressing type 2 immunity, in addition to exerting robust anti-tumor activities when used as a mono-therapeutic agent for cancer immunotherapy. Here, we sought the immunological mechanisms and found that their potent anti-tumor immunity in a Pan02 peritoneal dissemination model of pancreatic cancer was achieved only when agonist for TLR9 and STING were administered locally, and was via mechanisms involving CD4 and CD8 T cells as well as the co-operative action of IL-12 and type I IFNs. Rechallenge studies of long-term cancer survivors suggested that the elicitation of Pan02-specific memory responses provide protection against the secondary tumor challenge. Mechanistically, we found that TLR9 and STING agonists synergistically induce IL-12 and type I IFN production in murine APCs. The synergistic effect of the TLR9 and STING agonists on IL-12p40 was at protein, mRNA, and promoter activation levels, and transcriptional regulation was mediated by a 200 bp region situated 983 bp upstream of the IL-12p40 transcription initiation site. Such intracellular transcriptional synergy may hold a key in successful cancer immunotherapy and provide further insights into dual agonism of innate immune sensors during host homeostasis and diseases.
|
| Volume |
34(7)
|
| Pages |
353-364
|
| Published |
2022-7-4
|
| DOI |
10.1093/intimm/dxac012
|
| PII |
6568353
|
| PMID |
35419609
|
| MeSH |
Adjuvants, Immunologic / pharmacology
Animals
Immunotherapy
Interleukin-12
Interleukin-12 Subunit p40
Membrane Proteins* / metabolism
Mice
Neoplasms*
Toll-Like Receptor 9* / metabolism
|
| IF |
3.519
|
| Resource |
| Human and Animal Cells |
RAW 264(RCB0535) |
