A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment
Abstract All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implic...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-41690-5 |
| _version_ | 1827634309832376320 |
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| author | Cheng-Hsin Wei Lu Huang Blair Kreh Xiuxia Liu Liliya Tyutyunyk-Massey Masanori Kawakami Zibo Chen Mi Shi Serguei Kozlov King C. Chan Thorkell Andresson Mary Carrington Vidyasagar Vuligonda Martin E. Sanders Amir Horowitz Patrick Hwu Weiyi Peng Ethan Dmitrovsky Xi Liu |
| author_facet | Cheng-Hsin Wei Lu Huang Blair Kreh Xiuxia Liu Liliya Tyutyunyk-Massey Masanori Kawakami Zibo Chen Mi Shi Serguei Kozlov King C. Chan Thorkell Andresson Mary Carrington Vidyasagar Vuligonda Martin E. Sanders Amir Horowitz Patrick Hwu Weiyi Peng Ethan Dmitrovsky Xi Liu |
| author_sort | Cheng-Hsin Wei |
| collection | DOAJ |
| description | Abstract All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8+ T cell depletion antagonized ATRA’s anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA’s anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice—a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4+ T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4+ more than CD8+ T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers. |
| first_indexed | 2024-03-09T15:11:34Z |
| format | Article |
| id | doaj.art-3a6d32daebaf4a6c91b60abe62aa93bd |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:11:34Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3a6d32daebaf4a6c91b60abe62aa93bd2023-11-26T13:20:00ZengNature PortfolioScientific Reports2045-23222023-09-0113111410.1038/s41598-023-41690-5A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironmentCheng-Hsin Wei0Lu Huang1Blair Kreh2Xiuxia Liu3Liliya Tyutyunyk-Massey4Masanori Kawakami5Zibo Chen6Mi Shi7Serguei Kozlov8King C. Chan9Thorkell Andresson10Mary Carrington11Vidyasagar Vuligonda12Martin E. Sanders13Amir Horowitz14Patrick Hwu15Weiyi Peng16Ethan Dmitrovsky17Xi Liu18Molecular Pharmacology Program, Frederick National Laboratory for Cancer ResearchDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer CenterMolecular Pharmacology Program, Frederick National Laboratory for Cancer ResearchMolecular Pharmacology Program, Frederick National Laboratory for Cancer ResearchMolecular Pharmacology Program, Frederick National Laboratory for Cancer ResearchMolecular Pharmacology Program, Frederick National Laboratory for Cancer ResearchMolecular Pharmacology Program, Frederick National Laboratory for Cancer ResearchMolecular Pharmacology Program, Frederick National Laboratory for Cancer ResearchCenter for Advanced Preclinical ResearchProtein Characterization LaboratoryProtein Characterization LaboratoryBasic Science Program, Frederick National Laboratory for Cancer ResearchIo Therapeutics, Inc.Io Therapeutics, Inc.Icahn School of Medicine at Mount SinaiDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer CenterMolecular Pharmacology Program, Frederick National Laboratory for Cancer ResearchMolecular Pharmacology Program, Frederick National Laboratory for Cancer ResearchAbstract All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8+ T cell depletion antagonized ATRA’s anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA’s anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice—a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4+ T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4+ more than CD8+ T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers.https://doi.org/10.1038/s41598-023-41690-5 |
| spellingShingle | Cheng-Hsin Wei Lu Huang Blair Kreh Xiuxia Liu Liliya Tyutyunyk-Massey Masanori Kawakami Zibo Chen Mi Shi Serguei Kozlov King C. Chan Thorkell Andresson Mary Carrington Vidyasagar Vuligonda Martin E. Sanders Amir Horowitz Patrick Hwu Weiyi Peng Ethan Dmitrovsky Xi Liu A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment Scientific Reports |
| title | A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment |
| title_full | A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment |
| title_fullStr | A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment |
| title_full_unstemmed | A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment |
| title_short | A novel retinoic acid receptor-γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment |
| title_sort | novel retinoic acid receptor γ agonist antagonizes immune checkpoint resistance in lung cancers by altering the tumor immune microenvironment |
| url | https://doi.org/10.1038/s41598-023-41690-5 |
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