UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Classifying cGAS-STING Activity Links Chromosomal Instability with Immunotherapy Response in Metastatic Bladder Cancer

Sokač, Mateo; Ahrenfeldt, Johanne; Litchfield, Kevin; Watkins, Thomas BK; Knudsen, Michael; Dyrskjøt, Lars; Jakobsen, Martin R; (2022) Classifying cGAS-STING Activity Links Chromosomal Instability with Immunotherapy Response in Metastatic Bladder Cancer. Cancer Research Communications , 2 (8) pp. 762-771. 10.1158/2767-9764.CRC-22-0047. Green open access

[thumbnail of Classifying cGAS-STING Activity Links Chromosomal Instability with Immunotherapy Response in Metastatic Bladder Cancer.pdf]
Preview
PDF
Classifying cGAS-STING Activity Links Chromosomal Instability with Immunotherapy Response in Metastatic Bladder Cancer.pdf - Published Version

Download (3MB) | Preview

Abstract

UNLABELLED: The cGAS-STING pathway serves a critical role in anticancer therapy. Particularly, response to immunotherapy is likely driven by both active cGAS-STING signaling that attracts immune cells, and by the presence of cancer neoantigens that presents as targets for cytotoxic T cells. Chromosomal instability (CIN) is a hallmark of cancer, but also leads to an accumulation of cytosolic DNA that in turn results in increased cGAS-STING signaling. To avoid triggering the cGAS-STING pathway, it is commonly disrupted by cancer cells, either through mutations in the pathway or through transcriptional silencing. Given its effect on the immune system, determining the cGAS-STING activation status prior to treatment initiation is likely of clinical relevance. Here, we used combined expression data from 2,307 tumors from five cancer types from The Cancer Genome Atlas to define a novel cGAS-STING activity score based on eight genes with a known role in the pathway. Using unsupervised clustering, four distinct categories of cGAS-STING activation were identified. In multivariate models, the cGAS-STING active tumors show improved prognosis. Importantly, in an independent bladder cancer immunotherapy-treated cohort, patients with low cGAS-STING expression showed limited response to treatment, while patients with high expression showed improved response and prognosis, particularly among patients with high CIN and more neoantigens. In a multivariate model, a significant interaction was observed between CIN, neoantigens, and cGAS-STING activation. Together, this suggests a potential role of cGAS-STING activity as a predictive biomarker for the application of immunotherapy. SIGNIFICANCE: The cGAS-STING pathway is induced by CIN, triggers inflammation and is often deficient in cancer. We provide a tool to evaluate cGAS-STING activity and demonstrate clinical significance in immunotherapy response.

Type: Article
Title: Classifying cGAS-STING Activity Links Chromosomal Instability with Immunotherapy Response in Metastatic Bladder Cancer
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/2767-9764.CRC-22-0047
Publisher version: https://doi.org/10.1158/2767-9764.CRC-22-0047
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10167399
Downloads since deposit
9Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item