Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation.

Autor:	Alshebremi M; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia., Tomchuck SL; Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Myers JT; Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Kingsley DT; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Eid S; Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Abiff M; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Bonner M; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Saab ST; Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA., Choi SH; Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Huang AY; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA alex.y.huang@case.edu.; Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; Center for Pediatric Immunotherapy, Angie Fowler AYA Cancer Institute, UH Rainbow Babies & Children's Hospital, Cleveland, Ohio, USA.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Aug; Vol. 11 (8).
DOI:	10.1136/jitc-2022-006608
Abstrakt:	Background: Despite its potential utility in delivering direct tumor killing and in situ whole-cell tumor vaccination, tumor cryoablation produces highly variable and unpredictable clinical response, limiting its clinical utility. The mechanism(s) driving cryoablation-induced local antitumor immunity and the associated abscopal effect is not well understood. Methods: The aim of this study was to identify and explore a mechanism of action by which cryoablation enhances the therapeutic efficacy in metastatic tumor models. We used the subcutaneous mouse model of the rhabdomyosarcoma (RMS) cell lines RMS 76-9 STINGwt or RMS 76-9 STING-/- , along with other murine tumor models, in C57BL/6 or STING -/- ( TMEM173 -/- ) mice to evaluate local tumor changes, lung metastasis, abscopal effect on distant tumors, and immune cell dynamics in the tumor microenvironment (TME). Results: The results show that cryoablation efficacy is dependent on both adaptive immunity and the STING signaling pathway. Contrary to current literature dictating an essential role of host-derived STING activation as a driver of antitumor immunity in vivo, we show that local tumor control, lung metastasis, and the abscopal effect on distant tumor are all critically dependent on a functioning tumor cell-intrinsic STING signaling pathway, which induces inflammatory chemokine and cytokine responses in the cryoablated TME. This reliance extends beyond cryoablation to include intratumoral STING agonist therapy. Additionally, surveys of gene expression databases and tissue microarrays of clinical tumor samples revealed a wide spectrum of expressions among STING-related signaling components. Conclusions: Tumor cell-intrinsic STING pathway is a critical component underlying the effectiveness of cryoablation and suggests that expression of STING-related signaling components may serve as a potential therapy response biomarker. Our data also highlight an urgent need to further characterize tumor cell-intrinsic STING pathways and the associated downstream inflammatory response evoked by cryoablation and other STING-dependent therapy approaches. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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