Dataset Information

Activation of Tumor-Cell STING Primes NK-Cell Therapy.

ABSTRACT: Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.

SUBMITTER: Knelson EH

PROVIDER: S-EPMC9357206 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Activation of Tumor-Cell STING Primes NK-Cell Therapy.

Knelson Erik H EH Ivanova Elena V EV Tarannum Mubin M Campisi Marco M Lizotte Patrick H PH Booker Matthew A MA Ozgenc Ismail I Noureddine Moataz M Meisenheimer Brittany B Chen Minyue M Piel Brandon B Spicer Nathaniel N Obua Bonje B Messier Cameron M CM Shannon Erin E Mahadevan Navin R NR Tani Tetsuo T Schol Pieter J PJ Lee-Hassett Anna M AM Zlota Ari A Vo Ha V HV Ha Minh M Bertram Arrien A AA Han Saemi S Thai Tran C TC Gustafson Corinne E CE Venugopal Kartika K Haggerty Timothy J TJ Albertson Thomas P TP Hartley Antja-Voy AV Eser Pinar O PO Li Ze-Hua ZH Cañadas Israel I Vivero Marina M De Rienzo Assunta A Richards William G WG Abu-Yousif Adnan O AO Appleman Vicky A VA Gregory Richard C RC Parent Alexander A Lineberry Neil N Smith Eric L EL Jänne Pasi A PA Miret Juan J JJ Tolstorukov Michael Y MY Romee Rizwan R Paweletz Cloud P CP Bueno Raphael R Barbie David A DA

Cancer immunology research 20220801 8

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA se ...[more]

PMID: 35678717

Similar Datasets

Project description:BackgroundDespite 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.MethodsThe 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 76-9STINGwt or RMS 76-9STING-/-, 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).ResultsThe 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.ConclusionsTumor 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.

Dataset Information

Activation of Tumor-Cell STING Primes NK-Cell Therapy.

Publications

Activation of Tumor-Cell STING Primes NK-Cell Therapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets