CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma
Background Combination herpes simplex virus (HSV) oncolytic virotherapy and BRAF inhibitors (BRAFi) represent promising immunogenic treatments for BRAF mutant melanoma, but an improved understanding of the immunobiology of combinations is needed to improve on the benefit of immune checkpoint inhibit...
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004410.full |
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| author | Victoria Jennings Kevin Harrington Hardev Pandha Alan Melcher Adel Samson Fiona Errington-Mais Victoria Roulstone Eva Crespo-Rodriguez Galabina Bozhanova Shane Foo Emmanuel C Patin Martin McLaughlin Malin Pedersen Richard Vile Joan Kyula Jehanne Hassan Lizzie Appleton Charleen ML Chan Wah Hak Gabby Baker Edward Armstrong Matthew Chiu Masahiro Ono |
| author_facet | Victoria Jennings Kevin Harrington Hardev Pandha Alan Melcher Adel Samson Fiona Errington-Mais Victoria Roulstone Eva Crespo-Rodriguez Galabina Bozhanova Shane Foo Emmanuel C Patin Martin McLaughlin Malin Pedersen Richard Vile Joan Kyula Jehanne Hassan Lizzie Appleton Charleen ML Chan Wah Hak Gabby Baker Edward Armstrong Matthew Chiu Masahiro Ono |
| author_sort | Victoria Jennings |
| collection | DOAJ |
| description | Background Combination herpes simplex virus (HSV) oncolytic virotherapy and BRAF inhibitors (BRAFi) represent promising immunogenic treatments for BRAF mutant melanoma, but an improved understanding of the immunobiology of combinations is needed to improve on the benefit of immune checkpoint inhibitors (ICI).Methods Using a BRAFV600E-driven murine melanoma model, we tested the immunogenicity of HSV/BRAFi in immunocompetent C57BL mice. In addition to standard FACS analysis, we used the ‘Timer of Cell Kinetics and Activity’ system, which can analyze the temporal dynamics of different T cell subsets. This immune data was used to inform the selection of ICI for triple combination therapy, the effects of which were then further characterized using transcriptomics.Results Adding BRAFi treatment to HSV improved anti-tumor effects in vivo but not in vitro. Immune characterization showed HSV or dual therapy led to fewer intratumoral Treg, although with a more activated phenotype, together with more effector CD8 +T cells. Tocky analysis further showed that HSV/BRAFi dual treatment reduced the Tocky signal (reflecting engagement with cognate antigen), in both Treg and conventional subsets of CD4+, but not in CD8 +cells. However, a higher percentage of Treg than of conventional CD4 +maintained frequent engagement with antigens on treatment, reflecting a predominance of suppressive over effector function within the CD4 +compartment. The only T cell subset which correlated with a reduction in tumor growth was within Tocky signal positive conventional CD4+, supporting their therapeutic role. Targeting CD25 high, antigen-engaged Treg with a depleting anti-CD25 ICI, achieved complete cures in 100% of mice with triple therapy. Transcriptomic analysis confirmed reduction in Foxp3 on addition of anti-CD25 to HSV/BRAFi, as well as increases in expression of genes reflecting interferon signaling and cytotoxic activity.Conclusions Combination HSV/BRAFi is an immunogenic therapy for BRAF mutant melanoma, but cannot fully control tumors. Dual therapy results in changes in T cell dynamics within tumors, with relatively maintained antigen signaling in Treg compared with conv CD4+. Antigen-engaged CD4 +effectors correlate with tumor growth control, and depletion of Treg by addition of an anti-CD25 ICI, releasing suppression of conventional CD4 +effectors by Treg, enhances survival and activates immune signaling within tumors. |
| format | Article |
| id | doaj-art-316204113b0e4019ac28423a26ae7cf2 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-316204113b0e4019ac28423a26ae7cf22025-02-09T16:55:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004410CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanomaVictoria Jennings0Kevin Harrington1Hardev Pandha2Alan Melcher3Adel Samson4Fiona Errington-Mais5Victoria Roulstone6Eva Crespo-Rodriguez7Galabina Bozhanova8Shane Foo9Emmanuel C Patin10Martin McLaughlin11Malin Pedersen12Richard Vile13Joan Kyula14Jehanne Hassan15Lizzie Appleton16Charleen ML Chan Wah Hak17Gabby Baker18Edward Armstrong19Matthew Chiu20Masahiro Ono21Leeds Institute of Medical Research, University of Leeds, Leeds, UK11 Targeted Therapy Team, The Institute of Cancer Research, London, UKDepartment of Clinical and Experimental Medicine, University of Surrey, Guildford, UKDivision of Radiotherapy and Imaging, The Institute of Cancer Research, London, UKLeeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, UKLeeds Institute of Medical Research at St James`s, University of Leeds, Leeds, UKThe Institute of Cancer Research, London, UKTranslational Immunotherapy/Targeted Therapy Teams, The Institute of Cancer Research, London, UKTranslational Immunotherapy/Targeted Therapy Teams, The Institute of Cancer Research, London, UKDivision of Radiotherapy and Imaging, The Institute of Cancer Research, London, UKTranslational Immunotherapy/Targeted Therapy Teams, The Institute of Cancer Research, London, UKDivision of Radiotherapy and Imaging, The Institute of Cancer Research, London, UKDivision of Radiotherapy and Imaging, The Institute of Cancer Research, London, UKDepartment of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USAThe Institute of Cancer Research, London, UKImperial College London, London, UKImperial College London, London, London, UKTranslational Immunotherapy/Targeted Therapy Teams, The Institute of Cancer Research, London, UKTranslational Immunotherapy/Targeted Therapy Teams, The Institute of Cancer Research, London, UKDivision of Radiotherapy and Imaging, The Institute of Cancer Research, London, UKTranslational Immunotherapy/Targeted Therapy Teams, The Institute of Cancer Research, London, UKImperial College London, London, London, UKBackground Combination herpes simplex virus (HSV) oncolytic virotherapy and BRAF inhibitors (BRAFi) represent promising immunogenic treatments for BRAF mutant melanoma, but an improved understanding of the immunobiology of combinations is needed to improve on the benefit of immune checkpoint inhibitors (ICI).Methods Using a BRAFV600E-driven murine melanoma model, we tested the immunogenicity of HSV/BRAFi in immunocompetent C57BL mice. In addition to standard FACS analysis, we used the ‘Timer of Cell Kinetics and Activity’ system, which can analyze the temporal dynamics of different T cell subsets. This immune data was used to inform the selection of ICI for triple combination therapy, the effects of which were then further characterized using transcriptomics.Results Adding BRAFi treatment to HSV improved anti-tumor effects in vivo but not in vitro. Immune characterization showed HSV or dual therapy led to fewer intratumoral Treg, although with a more activated phenotype, together with more effector CD8 +T cells. Tocky analysis further showed that HSV/BRAFi dual treatment reduced the Tocky signal (reflecting engagement with cognate antigen), in both Treg and conventional subsets of CD4+, but not in CD8 +cells. However, a higher percentage of Treg than of conventional CD4 +maintained frequent engagement with antigens on treatment, reflecting a predominance of suppressive over effector function within the CD4 +compartment. The only T cell subset which correlated with a reduction in tumor growth was within Tocky signal positive conventional CD4+, supporting their therapeutic role. Targeting CD25 high, antigen-engaged Treg with a depleting anti-CD25 ICI, achieved complete cures in 100% of mice with triple therapy. Transcriptomic analysis confirmed reduction in Foxp3 on addition of anti-CD25 to HSV/BRAFi, as well as increases in expression of genes reflecting interferon signaling and cytotoxic activity.Conclusions Combination HSV/BRAFi is an immunogenic therapy for BRAF mutant melanoma, but cannot fully control tumors. Dual therapy results in changes in T cell dynamics within tumors, with relatively maintained antigen signaling in Treg compared with conv CD4+. Antigen-engaged CD4 +effectors correlate with tumor growth control, and depletion of Treg by addition of an anti-CD25 ICI, releasing suppression of conventional CD4 +effectors by Treg, enhances survival and activates immune signaling within tumors.https://jitc.bmj.com/content/10/3/e004410.full |
| spellingShingle | Victoria Jennings Kevin Harrington Hardev Pandha Alan Melcher Adel Samson Fiona Errington-Mais Victoria Roulstone Eva Crespo-Rodriguez Galabina Bozhanova Shane Foo Emmanuel C Patin Martin McLaughlin Malin Pedersen Richard Vile Joan Kyula Jehanne Hassan Lizzie Appleton Charleen ML Chan Wah Hak Gabby Baker Edward Armstrong Matthew Chiu Masahiro Ono CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma Journal for ImmunoTherapy of Cancer |
| title | CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma |
| title_full | CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma |
| title_fullStr | CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma |
| title_full_unstemmed | CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma |
| title_short | CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma |
| title_sort | cd4 t cell dynamics shape the immune response to combination oncolytic herpes virus and braf inhibitor therapy for melanoma |
| url | https://jitc.bmj.com/content/10/3/e004410.full |
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