Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1
Despite breakthroughs in immune checkpoint inhibitors (ICI), the majority of tumors, including those poorly infiltrated by CD8+ T cells or heavily infiltrated by immunosuppressive immune effector cells, are unlikely to result in clinically meaningful tumor responses. Radiation therapy (RT) has been...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2223094 |
| _version_ | 1826914943792840704 |
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| author | Debayan Mukherjee Erminia Romano Richard Walshaw Leo A. H. Zeef Antonia Banyard Stephen J. Kitcatt Eleanor J. Cheadle Karoliina Tuomela Swati Pendharkar Aws Al-Deka Beatrice Salerno Sophie Raby Ian G. Mills Jamie Honeychurch Tim M. Illidge |
| author_facet | Debayan Mukherjee Erminia Romano Richard Walshaw Leo A. H. Zeef Antonia Banyard Stephen J. Kitcatt Eleanor J. Cheadle Karoliina Tuomela Swati Pendharkar Aws Al-Deka Beatrice Salerno Sophie Raby Ian G. Mills Jamie Honeychurch Tim M. Illidge |
| author_sort | Debayan Mukherjee |
| collection | DOAJ |
| description | Despite breakthroughs in immune checkpoint inhibitors (ICI), the majority of tumors, including those poorly infiltrated by CD8+ T cells or heavily infiltrated by immunosuppressive immune effector cells, are unlikely to result in clinically meaningful tumor responses. Radiation therapy (RT) has been combined with ICI to potentially overcome this resistance and improve response rates but reported clinical trial results have thus far been disappointing. Novel approaches are required to overcome this resistance and reprogram the immunosuppressive tumor microenvironment (TME) and address this major unmet clinical need. Using diverse preclinical tumor models of prostate and bladder cancer, including an autochthonous prostate tumor (Pten−/−/trp53−/−) that respond poorly to radiation therapy (RT) and anti-PD-L1 combinations, the key drivers of this resistance within the TME were profiled and used to develop rationalized combination therapies that simultaneously enhance activation of anti-cancer T cell responses and reprogram the immunosuppressive TME. The addition of anti-CD40mAb to RT resulted in an increase in IFN-y signaling, activation of Th−1 pathways with an increased infiltration of CD8+ T-cells and regulatory T-cells with associated activation of the CTLA−4 signaling pathway in the TME. Anti-CTLA−4mAb in combination with RT further reprogrammed the immunosuppressive TME, resulting in durable, long-term tumor control. Our data provide novel insights into the underlying mechanisms of the immunosuppressive TME that result in resistance to RT and anti-PD−1 inhibitors and inform therapeutic approaches to reprogramming the immune contexture in the TME to potentially improve tumor responses and clinical outcomes. |
| first_indexed | 2024-03-08T17:13:06Z |
| format | Article |
| id | doaj.art-9f867c6013ac405080b84ec982759eae |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2025-02-17T11:52:28Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-9f867c6013ac405080b84ec982759eae2024-12-27T17:34:39ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2023.2223094Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1Debayan Mukherjee0Erminia Romano1Richard Walshaw2Leo A. H. Zeef3Antonia Banyard4Stephen J. Kitcatt5Eleanor J. Cheadle6Karoliina Tuomela7Swati Pendharkar8Aws Al-Deka9Beatrice Salerno10Sophie Raby11Ian G. Mills12Jamie Honeychurch13Tim M. Illidge14Targeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKBioinformatics Core Facility, Michael Smith Building, The University of Manchester, Manchester, UKMass and Flow Cytometry Core Facility, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UKScientific Computing Core Facility, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKNuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UKDespite breakthroughs in immune checkpoint inhibitors (ICI), the majority of tumors, including those poorly infiltrated by CD8+ T cells or heavily infiltrated by immunosuppressive immune effector cells, are unlikely to result in clinically meaningful tumor responses. Radiation therapy (RT) has been combined with ICI to potentially overcome this resistance and improve response rates but reported clinical trial results have thus far been disappointing. Novel approaches are required to overcome this resistance and reprogram the immunosuppressive tumor microenvironment (TME) and address this major unmet clinical need. Using diverse preclinical tumor models of prostate and bladder cancer, including an autochthonous prostate tumor (Pten−/−/trp53−/−) that respond poorly to radiation therapy (RT) and anti-PD-L1 combinations, the key drivers of this resistance within the TME were profiled and used to develop rationalized combination therapies that simultaneously enhance activation of anti-cancer T cell responses and reprogram the immunosuppressive TME. The addition of anti-CD40mAb to RT resulted in an increase in IFN-y signaling, activation of Th−1 pathways with an increased infiltration of CD8+ T-cells and regulatory T-cells with associated activation of the CTLA−4 signaling pathway in the TME. Anti-CTLA−4mAb in combination with RT further reprogrammed the immunosuppressive TME, resulting in durable, long-term tumor control. Our data provide novel insights into the underlying mechanisms of the immunosuppressive TME that result in resistance to RT and anti-PD−1 inhibitors and inform therapeutic approaches to reprogramming the immune contexture in the TME to potentially improve tumor responses and clinical outcomes.https://www.tandfonline.com/doi/10.1080/2162402X.2023.2223094RadiotherapyimmunotherapyTregsimmune Checkpoints |
| spellingShingle | Debayan Mukherjee Erminia Romano Richard Walshaw Leo A. H. Zeef Antonia Banyard Stephen J. Kitcatt Eleanor J. Cheadle Karoliina Tuomela Swati Pendharkar Aws Al-Deka Beatrice Salerno Sophie Raby Ian G. Mills Jamie Honeychurch Tim M. Illidge Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1 OncoImmunology Radiotherapy immunotherapy Tregs immune Checkpoints |
| title | Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1 |
| title_full | Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1 |
| title_fullStr | Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1 |
| title_full_unstemmed | Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1 |
| title_short | Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1 |
| title_sort | reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti pd 1 pd l1 |
| topic | Radiotherapy immunotherapy Tregs immune Checkpoints |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2223094 |
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