TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response
Background Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the resp...
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BMJ Publishing Group
2024-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/7/e008739.full |
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| author | Saraí G De León-Rodríguez Cristina Aguilar-Flores Julián A Gajón Ángel Juárez-Flores Alejandra Mantilla Raquel Gerson-Cwilich José Fabián Martínez-Herrera Diana Alejandra Villegas-Osorno Claudia T Gutiérrez-Quiroz Sergio Buenaventura-Cisneros Mario Alberto Sánchez-Prieto Edmundo Castelán-Maldonado Samuel Rivera Rivera Ezequiel M Fuentes-Pananá Laura C Bonifaz |
| author_facet | Saraí G De León-Rodríguez Cristina Aguilar-Flores Julián A Gajón Ángel Juárez-Flores Alejandra Mantilla Raquel Gerson-Cwilich José Fabián Martínez-Herrera Diana Alejandra Villegas-Osorno Claudia T Gutiérrez-Quiroz Sergio Buenaventura-Cisneros Mario Alberto Sánchez-Prieto Edmundo Castelán-Maldonado Samuel Rivera Rivera Ezequiel M Fuentes-Pananá Laura C Bonifaz |
| author_sort | Saraí G De León-Rodríguez |
| collection | DOAJ |
| description | Background Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7+ (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation.Methods We used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders.Results Our study identifies two CD8+TRM subsets, TCF1+ and TCF1−, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1− TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1− subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1− TRM/cDC1 pairs in tumor areas. Notably, these TCF1− TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1− TRM subsets, alongside cDC1, prove relevant to CBI response.Conclusions Our study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1− TRM subsets, both crucial for melanoma control and CBI response. |
| format | Article |
| id | doaj-art-8ab5aa2af15e4a039c6dff460d7a7344 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-8ab5aa2af15e4a039c6dff460d7a73442025-02-09T02:05:15ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-07-0112710.1136/jitc-2023-008739TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy responseSaraí G De León-Rodríguez0Cristina Aguilar-Flores1Julián A Gajón2Ángel Juárez-Flores3Alejandra Mantilla4Raquel Gerson-Cwilich5José Fabián Martínez-Herrera6Diana Alejandra Villegas-Osorno7Claudia T Gutiérrez-Quiroz8Sergio Buenaventura-Cisneros9Mario Alberto Sánchez-Prieto10Edmundo Castelán-Maldonado11Samuel Rivera Rivera12Ezequiel M Fuentes-Pananá13Laura C Bonifaz14Unidad de Investigación Médica en Inmunoquímica, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de Mexico, MexicoUnidad de Investigación Médica en Inmunología, UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de Mexico, MexicoUnidad de Investigación Médica en Inmunoquímica, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de Mexico, MexicoUnidad de Investigación Médica en Inmunoquímica, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de Mexico, MexicoServicio de Patología, Hospital de Oncología Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de Mexico, MexicoMedical Center American British Cowdray, Mexico City, MexicoMedical Center American British Cowdray, Mexico City, MexicoMedical Center American British Cowdray, Mexico City, MexicoUMAE Hospital de Especialidades, Centro Médico Nacional General Manuel Avila Camacho, Instituto Mexicano del Seguro Social, Puebla, MexicoUnidad Médica de Alta Especialidad No.25, Instituto Mexicano del Seguro Social, Monterrey, Nuevo Leon, MexicoUnidad Médica de Alta Especialidad No.25, Instituto Mexicano del Seguro Social, Monterrey, Nuevo Leon, MexicoUnidad Médica de Alta Especialidad No.25, Instituto Mexicano del Seguro Social, Monterrey, Nuevo Leon, MexicoMedical Center American British Cowdray, Mexico City, MexicoUnidad de Investigación en Virología y Cáncer, Hospital Infantil de Mexico Federico Gomez, Mexico City, MexicoUnidad de Investigación Médica en Inmunoquímica, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de Mexico, MexicoBackground Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7+ (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation.Methods We used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders.Results Our study identifies two CD8+TRM subsets, TCF1+ and TCF1−, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1− TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1− subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1− TRM/cDC1 pairs in tumor areas. Notably, these TCF1− TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1− TRM subsets, alongside cDC1, prove relevant to CBI response.Conclusions Our study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1− TRM subsets, both crucial for melanoma control and CBI response.https://jitc.bmj.com/content/12/7/e008739.full |
| spellingShingle | Saraí G De León-Rodríguez Cristina Aguilar-Flores Julián A Gajón Ángel Juárez-Flores Alejandra Mantilla Raquel Gerson-Cwilich José Fabián Martínez-Herrera Diana Alejandra Villegas-Osorno Claudia T Gutiérrez-Quiroz Sergio Buenaventura-Cisneros Mario Alberto Sánchez-Prieto Edmundo Castelán-Maldonado Samuel Rivera Rivera Ezequiel M Fuentes-Pananá Laura C Bonifaz TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response Journal for ImmunoTherapy of Cancer |
| title | TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response |
| title_full | TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response |
| title_fullStr | TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response |
| title_full_unstemmed | TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response |
| title_short | TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response |
| title_sort | tcf1 positive and tcf1 negative trm cd8 t cell subsets and cdc1s orchestrate melanoma protection and immunotherapy response |
| url | https://jitc.bmj.com/content/12/7/e008739.full |
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