A novel small molecule Enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal Enpp1 expression
Abstract The uniqueness in each person’s cancer cells and variation in immune infiltrates means that each tumor represents a unique problem, but therapeutic targets can be found among their shared features. Radiation therapy alters the interaction between the cancer cells and the stroma through rele...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-80677-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850169226969481216 |
|---|---|
| author | Jason R Baird Alejandro F Alice Roland Saito Qingqing Chai Minhua Han Cindy Ng Stephanie Han Beth Fernandez Sarah Ledoux Johannes Grosse Alan J Korman Megan Potuznik Venkatesh Rajamanickam Brady Bernard Marka R Crittenden Michael J Gough |
| author_facet | Jason R Baird Alejandro F Alice Roland Saito Qingqing Chai Minhua Han Cindy Ng Stephanie Han Beth Fernandez Sarah Ledoux Johannes Grosse Alan J Korman Megan Potuznik Venkatesh Rajamanickam Brady Bernard Marka R Crittenden Michael J Gough |
| author_sort | Jason R Baird |
| collection | DOAJ |
| description | Abstract The uniqueness in each person’s cancer cells and variation in immune infiltrates means that each tumor represents a unique problem, but therapeutic targets can be found among their shared features. Radiation therapy alters the interaction between the cancer cells and the stroma through release of innate adjuvants. The extranuclear DNA that can result from radiation damage of cells can result in production of the second messenger cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) by cyclic GMP-AMP synthase (cGAS). In turn, cGAMP can activate the innate sensor stimulator of interferon genes (STING), resulting in innate immune activation. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is a phosphodiesterase that can be expressed by cancer cells that can degrade cGAMP, thus can decrease or block STING activation following radiation therapy, impairing the innate immunity that is critical to support adaptive immune control of tumors. We observed that many human and murine cancer cells lack Enpp1 expression, but that Enpp1 is expressed in cells of the tumor stroma where it limits tumor control by radiation therapy. We demonstrate in preclinical models the efficacy of a novel Enpp1 inhibitor and show that this inhibitor improves tumor control by radiation even where the cancer cells lack Enpp1. This mechanism requires STING and type I interferon (IFN) receptor expression by non-cancer cells and is dependent on CD8 T cells as a final effector mechanism of tumor control. This suggests that Enpp1 inhibition may be an effective partner for radiation therapy regardless of whether cancer cells express Enpp1. This broadens the potential patient base for whom Enpp1 inhibitors can be applied to improve innate immune responses following radiation therapy. |
| format | Article |
| id | doaj-art-cbaeda0ee181438bbb8d05f9ec45b660 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-cbaeda0ee181438bbb8d05f9ec45b6602025-08-20T02:20:45ZengNature PortfolioScientific Reports2045-23222024-12-0114111710.1038/s41598-024-80677-8A novel small molecule Enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal Enpp1 expressionJason R Baird0Alejandro F Alice1Roland Saito2Qingqing Chai3Minhua Han4Cindy Ng5Stephanie Han6Beth Fernandez7Sarah Ledoux8Johannes Grosse9Alan J Korman10Megan Potuznik11Venkatesh Rajamanickam12Brady Bernard13Marka R Crittenden14Michael J Gough15Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical CenterEarle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical CenterVIR Biotechnology IncVIR Biotechnology IncVIR Biotechnology IncVIR Biotechnology IncVIR Biotechnology IncVIR Biotechnology IncVIR Biotechnology IncVIR Biotechnology IncVIR Biotechnology IncEarle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical CenterEarle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical CenterEarle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical CenterEarle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical CenterEarle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical CenterAbstract The uniqueness in each person’s cancer cells and variation in immune infiltrates means that each tumor represents a unique problem, but therapeutic targets can be found among their shared features. Radiation therapy alters the interaction between the cancer cells and the stroma through release of innate adjuvants. The extranuclear DNA that can result from radiation damage of cells can result in production of the second messenger cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) by cyclic GMP-AMP synthase (cGAS). In turn, cGAMP can activate the innate sensor stimulator of interferon genes (STING), resulting in innate immune activation. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is a phosphodiesterase that can be expressed by cancer cells that can degrade cGAMP, thus can decrease or block STING activation following radiation therapy, impairing the innate immunity that is critical to support adaptive immune control of tumors. We observed that many human and murine cancer cells lack Enpp1 expression, but that Enpp1 is expressed in cells of the tumor stroma where it limits tumor control by radiation therapy. We demonstrate in preclinical models the efficacy of a novel Enpp1 inhibitor and show that this inhibitor improves tumor control by radiation even where the cancer cells lack Enpp1. This mechanism requires STING and type I interferon (IFN) receptor expression by non-cancer cells and is dependent on CD8 T cells as a final effector mechanism of tumor control. This suggests that Enpp1 inhibition may be an effective partner for radiation therapy regardless of whether cancer cells express Enpp1. This broadens the potential patient base for whom Enpp1 inhibitors can be applied to improve innate immune responses following radiation therapy.https://doi.org/10.1038/s41598-024-80677-8 |
| spellingShingle | Jason R Baird Alejandro F Alice Roland Saito Qingqing Chai Minhua Han Cindy Ng Stephanie Han Beth Fernandez Sarah Ledoux Johannes Grosse Alan J Korman Megan Potuznik Venkatesh Rajamanickam Brady Bernard Marka R Crittenden Michael J Gough A novel small molecule Enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal Enpp1 expression Scientific Reports |
| title | A novel small molecule Enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal Enpp1 expression |
| title_full | A novel small molecule Enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal Enpp1 expression |
| title_fullStr | A novel small molecule Enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal Enpp1 expression |
| title_full_unstemmed | A novel small molecule Enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal Enpp1 expression |
| title_short | A novel small molecule Enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal Enpp1 expression |
| title_sort | novel small molecule enpp1 inhibitor improves tumor control following radiation therapy by targeting stromal enpp1 expression |
| url | https://doi.org/10.1038/s41598-024-80677-8 |
| work_keys_str_mv | AT jasonrbaird anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT alejandrofalice anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT rolandsaito anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT qingqingchai anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT minhuahan anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT cindyng anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT stephaniehan anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT bethfernandez anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT sarahledoux anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT johannesgrosse anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT alanjkorman anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT meganpotuznik anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT venkateshrajamanickam anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT bradybernard anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT markarcrittenden anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT michaeljgough anovelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT jasonrbaird novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT alejandrofalice novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT rolandsaito novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT qingqingchai novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT minhuahan novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT cindyng novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT stephaniehan novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT bethfernandez novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT sarahledoux novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT johannesgrosse novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT alanjkorman novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT meganpotuznik novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT venkateshrajamanickam novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT bradybernard novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT markarcrittenden novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression AT michaeljgough novelsmallmoleculeenpp1inhibitorimprovestumorcontrolfollowingradiationtherapybytargetingstromalenpp1expression |