Cytosolic bacterial pathogens activate TLR pathways in tumors that synergistically enhance STING agonist cancer therapies.

Autor:	Danielson M; Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA USA., Nicolai CJ; Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA., Vo TT; Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA USA., Wolf N; Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA., Burke TP; Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 02. Date of Electronic Publication: 2024 Feb 02.
DOI:	10.1101/2024.01.30.578087
Abstrakt:	Bacterial pathogens that invade the eukaryotic cytosol are distinctive tools for fighting cancer, as they preferentially target tumors and can deliver cancer antigens to MHC-I. Cytosolic bacterial pathogens have undergone extensive preclinical development and human clinical trials, yet the molecular mechanisms by which they are detected by innate immunity in tumors is unclear. We report that intratumoral delivery of phylogenetically distinct cytosolic pathogens, including Listeria, Rickettsia, and Burkholderia species, elicited anti-tumor responses in established, poorly immunogenic melanoma and lymphoma in mice. We were surprised to observe that although the bacteria required entry to the cytosol, the anti-tumor responses were largely independent of the cytosolic sensors cGAS/STING and instead required TLR signaling. Combining pathogens with TLR agonists did not enhance anti-tumor efficacy, while combinations with STING agonists elicited profound, synergistic anti-tumor effects with complete responses in >80% of mice after a single dose. Small molecule TLR agonists also synergistically enhanced the anti-tumor activity of STING agonists. The anti-tumor effects were diminished in Rag2 -deficient mice and upon CD8 T cell depletion. Mice cured from combination therapy developed immunity to cancer rechallenge that was superior to STING agonist monotherapy. Together, these data provide a framework for enhancing the efficacy of microbial cancer therapies and small molecule innate immune agonists, via the co-activation of STING and TLRs. Competing Interests: Competing interests T.P.B. is the co-founder of Bactonix Biotechnologies, Inc and serves or served its board of directors; he has financial interests in this company and could benefit from the commercialization of the results of this research. All other authors have no competing interests.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu