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Supplementary Data from Activation of Tumor-Cell STING Primes NK-Cell Therapy

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posted on 2023-04-04, 01:43 authored by Erik H. Knelson, Elena V. Ivanova, Mubin Tarannum, Marco Campisi, Patrick H. Lizotte, Matthew A. Booker, Ismail Ozgenc, Moataz Noureddine, Brittany Meisenheimer, Minyue Chen, Brandon Piel, Nathaniel Spicer, Bonje Obua, Cameron M. Messier, Erin Shannon, Navin R. Mahadevan, Tetsuo Tani, Pieter J. Schol, Anna M. Lee-Hassett, Ari Zlota, Ha V. Vo, Minh Ha, Arrien A. Bertram, Saemi Han, Tran C. Thai, Corinne E. Gustafson, Kartika Venugopal, Timothy J. Haggerty, Thomas P. Albertson, Antja-Voy Hartley, Pinar O. Eser, Ze-Hua Li, Israel Cañadas, Marina Vivero, Assunta De Rienzo, William G. Richards, Adnan O. Abu-Yousif, Vicky A. Appleman, Richard C. Gregory, Alexander Parent, Neil Lineberry, Eric L. Smith, Pasi A. Jänne, Juan J. Miret, Michael Y. Tolstorukov, Rizwan Romee, Cloud P. Paweletz, Raphael Bueno, David A. Barbie
Supplementary Data from Activation of Tumor-Cell STING Primes NK-Cell Therapy

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NCI

NIH

Research Agreement

Belgian Federal Science Policy Office

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ARTICLE 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.

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    Cancer Immunology Research

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    cancer

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    CC BY

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