TUMOR-INFILTRATING NOCICEPTOR NEURONS PROMOTE IMMUNOSUPPRESSION.

Autor:	Restaino AC; Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, USA., Ahmadi M; Department of Biomedical and Molecular Sciences, Queen's University. Kingston. Canada., Nikpoor AR; Department of Biomedical and Molecular Sciences, Queen's University. Kingston. Canada., Walz A; Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, USA., Balood M; Department of Biomedical and Molecular Sciences, Queen's University. Kingston. Canada., Eichwald T; Department of Biomedical and Molecular Sciences, Queen's University. Kingston. Canada.; Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden., Talbot S; Department of Biomedical and Molecular Sciences, Queen's University. Kingston. Canada.; Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden., Vermeer PD; Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 26. Date of Electronic Publication: 2024 Aug 26.
DOI:	10.1101/2024.08.23.609450
Abstrakt:	Nociceptor neurons impact tumor immunity. Removing nociceptor neurons reduced myeloid-derived suppressor cell (MDSCs) tumor infiltration in mouse models of head and neck carcinoma and melanoma. Carcinoma-released small extracellular vesicles (sEVs) attract nociceptive nerves to tumors. sEV-deficient tumors fail to develop in mice lacking nociceptor neurons. Exposure of dorsal root ganglia (DRG) neurons to cancer sEVs elevated expression of Substance P, IL-6 and injury-related neuronal markers while treatment with cancer sEVs and cytotoxic CD8 T-cells induced an immunosuppressive state (increased exhaustion ligands and cytokines). Cancer patient sEVs enhanced DRG responses to capsaicin, indicating increased nociceptor sensitivity. Conditioned media from DRG and cancer cell co-cultures promoted expression of MDSC markers in primary bone marrow cells while DRG conditioned media together with cancer sEVs induced checkpoint expression on T-cells. Our findings indicate that nociceptor neurons facilitate CD8+ T cell exhaustion and enhance MDSC infiltration. Targeting nociceptor-released IL-6 emerges as a novel strategy to disrupt harmful neuro-immune interactions in cancer and enhance anti-tumor immunity. Competing Interests: Sebastien Talbot is a minority stake holder in Nocion Therapeutics and received funding from Nocion Therapeutics and Cygnal Therapeutics. All other authors declare they have no competing interests.
Databáze:	MEDLINE
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