Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy
With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.849793/full |
| _version_ | 1830229926271254528 |
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| author | Caitlin M. Tilsed Caitlin M. Tilsed Thomas H. Casey Thomas H. Casey Emma de Jong Anthony Bosco Rachael M. Zemek Joanne Salmons Joanne Salmons Graeme Wan Graeme Wan Michael J. Millward Michael J. Millward Anna K. Nowak Anna K. Nowak Anna K. Nowak Richard A. Lake Richard A. Lake Willem Joost Lesterhuis Willem Joost Lesterhuis Willem Joost Lesterhuis |
| author_facet | Caitlin M. Tilsed Caitlin M. Tilsed Thomas H. Casey Thomas H. Casey Emma de Jong Anthony Bosco Rachael M. Zemek Joanne Salmons Joanne Salmons Graeme Wan Graeme Wan Michael J. Millward Michael J. Millward Anna K. Nowak Anna K. Nowak Anna K. Nowak Richard A. Lake Richard A. Lake Willem Joost Lesterhuis Willem Joost Lesterhuis Willem Joost Lesterhuis |
| author_sort | Caitlin M. Tilsed |
| collection | DOAJ |
| description | With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, hampering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further amplified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT. |
| first_indexed | 2024-12-18T10:44:23Z |
| format | Article |
| id | doaj.art-19eeddb4bf7541cbb0eb578d199bb0ef |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-18T10:44:23Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-19eeddb4bf7541cbb0eb578d199bb0ef2022-12-21T21:10:34ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-03-011210.3389/fonc.2022.849793849793Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint TherapyCaitlin M. Tilsed0Caitlin M. Tilsed1Thomas H. Casey2Thomas H. Casey3Emma de Jong4Anthony Bosco5Rachael M. Zemek6Joanne Salmons7Joanne Salmons8Graeme Wan9Graeme Wan10Michael J. Millward11Michael J. Millward12Anna K. Nowak13Anna K. Nowak14Anna K. Nowak15Richard A. Lake16Richard A. Lake17Willem Joost Lesterhuis18Willem Joost Lesterhuis19Willem Joost Lesterhuis20School of Biomedical Sciences, University of Western Australia, Crawley, WA, AustraliaNational Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, AustraliaSchool of Biomedical Sciences, University of Western Australia, Crawley, WA, AustraliaNational Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, AustraliaTelethon Kids Institute, University of Western Australia, Nedlands, WA, AustraliaTelethon Kids Institute, University of Western Australia, Nedlands, WA, AustraliaTelethon Kids Institute, University of Western Australia, Nedlands, WA, AustraliaSchool of Biomedical Sciences, University of Western Australia, Crawley, WA, AustraliaNational Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, AustraliaSchool of Biomedical Sciences, University of Western Australia, Crawley, WA, AustraliaNational Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, AustraliaMedical School, University of Western Australia, Crawley, WA, AustraliaDepartment of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, AustraliaNational Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, AustraliaMedical School, University of Western Australia, Crawley, WA, AustraliaDepartment of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, AustraliaSchool of Biomedical Sciences, University of Western Australia, Crawley, WA, AustraliaNational Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, AustraliaSchool of Biomedical Sciences, University of Western Australia, Crawley, WA, AustraliaNational Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, AustraliaTelethon Kids Institute, University of Western Australia, Nedlands, WA, AustraliaWith immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, hampering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further amplified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT.https://www.frontiersin.org/articles/10.3389/fonc.2022.849793/fullretinoic acidimmune checkpoint therapycancerinterferonmesothelioma |
| spellingShingle | Caitlin M. Tilsed Caitlin M. Tilsed Thomas H. Casey Thomas H. Casey Emma de Jong Anthony Bosco Rachael M. Zemek Joanne Salmons Joanne Salmons Graeme Wan Graeme Wan Michael J. Millward Michael J. Millward Anna K. Nowak Anna K. Nowak Anna K. Nowak Richard A. Lake Richard A. Lake Willem Joost Lesterhuis Willem Joost Lesterhuis Willem Joost Lesterhuis Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy Frontiers in Oncology retinoic acid immune checkpoint therapy cancer interferon mesothelioma |
| title | Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy |
| title_full | Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy |
| title_fullStr | Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy |
| title_full_unstemmed | Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy |
| title_short | Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy |
| title_sort | retinoic acid induces an ifn driven inflammatory tumour microenvironment sensitizing to immune checkpoint therapy |
| topic | retinoic acid immune checkpoint therapy cancer interferon mesothelioma |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.849793/full |
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