Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression
While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A f...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-12-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI158661 |
| _version_ | 1797634479751168000 |
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| author | Sean H. Colligan Andrea M. Amitrano Robert A. Zollo Jennifer Peresie Elliot D. Kramer Brian Morreale Joseph Barbi Prashant K. Singh Han Yu Jianmin Wang Mateusz Opyrchal David B. Sykes Michael J. Nemeth Scott I. Abrams |
| author_facet | Sean H. Colligan Andrea M. Amitrano Robert A. Zollo Jennifer Peresie Elliot D. Kramer Brian Morreale Joseph Barbi Prashant K. Singh Han Yu Jianmin Wang Mateusz Opyrchal David B. Sykes Michael J. Nemeth Scott I. Abrams |
| author_sort | Sean H. Colligan |
| collection | DOAJ |
| description | While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1–based (PD-1–based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8+ T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology. |
| first_indexed | 2024-03-11T12:09:24Z |
| format | Article |
| id | doaj.art-0a0122b323af493baa53eae9ada9561e |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:24Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-0a0122b323af493baa53eae9ada9561e2023-11-07T16:19:33ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-12-0113223Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progressionSean H. ColliganAndrea M. AmitranoRobert A. ZolloJennifer PeresieElliot D. KramerBrian MorrealeJoseph BarbiPrashant K. SinghHan YuJianmin WangMateusz OpyrchalDavid B. SykesMichael J. NemethScott I. AbramsWhile immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1–based (PD-1–based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8+ T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology.https://doi.org/10.1172/JCI158661Immunology |
| spellingShingle | Sean H. Colligan Andrea M. Amitrano Robert A. Zollo Jennifer Peresie Elliot D. Kramer Brian Morreale Joseph Barbi Prashant K. Singh Han Yu Jianmin Wang Mateusz Opyrchal David B. Sykes Michael J. Nemeth Scott I. Abrams Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression The Journal of Clinical Investigation Immunology |
| title | Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression |
| title_full | Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression |
| title_fullStr | Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression |
| title_full_unstemmed | Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression |
| title_short | Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression |
| title_sort | inhibiting the biogenesis of myeloid derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression |
| topic | Immunology |
| url | https://doi.org/10.1172/JCI158661 |
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