Cargando…

Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity

Type I interferon-mediated activation of immune cells can facilitate the generation of productive tumor antigen-specific T cell responses in solid tumors. The cGAS/STING DNA sensing pathway is a critical upstream mediator of type I interferon production and is an important regulator of anti-tumor im...

Descripción completa

Detalles Bibliográficos
Autores principales: Kim, Jennie C., Liu, Xian, Fitzgerald, Karen, Eng, Jason S., Orf, Jessica, O’Brien, Sarah A., Belmontes, Brian, Casbon, Amy-Jo, Novitskiy, Sergey V., Tarbell, Kristin V., DeVoss, Jason, Egen, Jackson G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110659/
https://www.ncbi.nlm.nih.gov/pubmed/36394642
http://dx.doi.org/10.1007/s00262-022-03327-w
_version_ 1785027307384078336
author Kim, Jennie C.
Liu, Xian
Fitzgerald, Karen
Eng, Jason S.
Orf, Jessica
O’Brien, Sarah A.
Belmontes, Brian
Casbon, Amy-Jo
Novitskiy, Sergey V.
Tarbell, Kristin V.
DeVoss, Jason
Egen, Jackson G.
author_facet Kim, Jennie C.
Liu, Xian
Fitzgerald, Karen
Eng, Jason S.
Orf, Jessica
O’Brien, Sarah A.
Belmontes, Brian
Casbon, Amy-Jo
Novitskiy, Sergey V.
Tarbell, Kristin V.
DeVoss, Jason
Egen, Jackson G.
author_sort Kim, Jennie C.
collection PubMed
description Type I interferon-mediated activation of immune cells can facilitate the generation of productive tumor antigen-specific T cell responses in solid tumors. The cGAS/STING DNA sensing pathway is a critical upstream mediator of type I interferon production and is an important regulator of anti-tumor immunity. Numerous STING pathway agonists are now being tested in clinical trials, but the effectiveness of this approach is not yet clear and a better understanding of the relative importance of this pathway in various tumor settings is needed. We have evaluated syngeneic tumor models with different baseline inflammatory states to determine the contributions of STING activity in both tumor and non-tumor cellular compartments to anti-tumor immune responses. We find that productive anti-tumor immune responses in the poorly immunogenic B16F10 model show a strong dependence on STING expression in non-tumor cells. In the immunogenic MC38 model, constitutive STING activation in tumor cells can partially bypass the requirement for STING-dependent activity from immune cells. Our findings reveal multiple, context-dependent roles for STING activity in the regulation of anti-tumor immunity and the response to immunotherapy. In preclinical models where STING is basally active, checkpoint inhibition is more likely to have a therapeutic effect and removal of STING signaling from either the tumor or the non-tumor compartment has a minimal effect. Removal of STING signaling in both, however, diminishes the efficacy derived from checkpoint therapy. Further work is needed to understand the heterogeneity of STING signaling in patients, both in tumor cells and the tumor microenvironment, and the best means of harnessing this pathway to generate anti-tumor immunity and improve therapeutic outcomes.
format Online
Article
Text
id pubmed-10110659
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-101106592023-04-19 Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity Kim, Jennie C. Liu, Xian Fitzgerald, Karen Eng, Jason S. Orf, Jessica O’Brien, Sarah A. Belmontes, Brian Casbon, Amy-Jo Novitskiy, Sergey V. Tarbell, Kristin V. DeVoss, Jason Egen, Jackson G. Cancer Immunol Immunother Brief Report Type I interferon-mediated activation of immune cells can facilitate the generation of productive tumor antigen-specific T cell responses in solid tumors. The cGAS/STING DNA sensing pathway is a critical upstream mediator of type I interferon production and is an important regulator of anti-tumor immunity. Numerous STING pathway agonists are now being tested in clinical trials, but the effectiveness of this approach is not yet clear and a better understanding of the relative importance of this pathway in various tumor settings is needed. We have evaluated syngeneic tumor models with different baseline inflammatory states to determine the contributions of STING activity in both tumor and non-tumor cellular compartments to anti-tumor immune responses. We find that productive anti-tumor immune responses in the poorly immunogenic B16F10 model show a strong dependence on STING expression in non-tumor cells. In the immunogenic MC38 model, constitutive STING activation in tumor cells can partially bypass the requirement for STING-dependent activity from immune cells. Our findings reveal multiple, context-dependent roles for STING activity in the regulation of anti-tumor immunity and the response to immunotherapy. In preclinical models where STING is basally active, checkpoint inhibition is more likely to have a therapeutic effect and removal of STING signaling from either the tumor or the non-tumor compartment has a minimal effect. Removal of STING signaling in both, however, diminishes the efficacy derived from checkpoint therapy. Further work is needed to understand the heterogeneity of STING signaling in patients, both in tumor cells and the tumor microenvironment, and the best means of harnessing this pathway to generate anti-tumor immunity and improve therapeutic outcomes. Springer Berlin Heidelberg 2022-11-17 2023 /pmc/articles/PMC10110659/ /pubmed/36394642 http://dx.doi.org/10.1007/s00262-022-03327-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Brief Report
Kim, Jennie C.
Liu, Xian
Fitzgerald, Karen
Eng, Jason S.
Orf, Jessica
O’Brien, Sarah A.
Belmontes, Brian
Casbon, Amy-Jo
Novitskiy, Sergey V.
Tarbell, Kristin V.
DeVoss, Jason
Egen, Jackson G.
Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity
title Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity
title_full Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity
title_fullStr Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity
title_full_unstemmed Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity
title_short Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity
title_sort brief report: sting expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110659/
https://www.ncbi.nlm.nih.gov/pubmed/36394642
http://dx.doi.org/10.1007/s00262-022-03327-w
work_keys_str_mv AT kimjenniec briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT liuxian briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT fitzgeraldkaren briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT engjasons briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT orfjessica briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT obriensaraha briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT belmontesbrian briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT casbonamyjo briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT novitskiysergeyv briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT tarbellkristinv briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT devossjason briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity
AT egenjacksong briefreportstingexpressedintumorandnontumorcompartmentshasdistinctrolesinregulatingantitumorimmunity