The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology
NKG2D is a major natural killer (NK) cell-activating receptor that recognizes eight ligands (NKG2DLs), including MICA, and whose engagement triggers NK cell effector functions. As NKG2DLs are upregulated on tumor cells but tumors can subvert the NKG2D-NKG2DL axis, NKG2DLs constitute attractive targe...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2104991 |
| _version_ | 1798038223670214656 |
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| author | Florencia Secchiari Sol Yanel Nuñez Jessica Mariel Sierra Andrea Ziblat María Victoria Regge Ximena Lucía Raffo Iraolagoitia Agustín Rovegno Carlos Ameri Fernando Pablo Secin Nicolás Richards Hernando Ríos Pita Gonzalo Vitagliano Luis Rico Mauro Mieggi Florencia Frascheri Nicolás Bonanno Leandro Blas Aldana Trotta Adrián David Friedrich Mercedes Beatriz Fuertes Carolina Inés Domaica Norberto Walter Zwirner |
| author_facet | Florencia Secchiari Sol Yanel Nuñez Jessica Mariel Sierra Andrea Ziblat María Victoria Regge Ximena Lucía Raffo Iraolagoitia Agustín Rovegno Carlos Ameri Fernando Pablo Secin Nicolás Richards Hernando Ríos Pita Gonzalo Vitagliano Luis Rico Mauro Mieggi Florencia Frascheri Nicolás Bonanno Leandro Blas Aldana Trotta Adrián David Friedrich Mercedes Beatriz Fuertes Carolina Inés Domaica Norberto Walter Zwirner |
| author_sort | Florencia Secchiari |
| collection | DOAJ |
| description | NKG2D is a major natural killer (NK) cell-activating receptor that recognizes eight ligands (NKG2DLs), including MICA, and whose engagement triggers NK cell effector functions. As NKG2DLs are upregulated on tumor cells but tumors can subvert the NKG2D-NKG2DL axis, NKG2DLs constitute attractive targets for antibody (Ab)-based immuno-oncology therapies. However, such approaches require a deep characterization of NKG2DLs and NKG2D cell surface expression on primary tumor and immune cells. Here, using a bioinformatic analysis, we observed that MICA is overexpressed in renal cell carcinoma (RCC), and we also detected an association between the NKG2D-MICA axis and a diminished overall survival of RCC patients. Also, by flow cytometry (FC), we observed that MICA was the only NKG2DL over-expressed on clear cell renal cell carcinoma (ccRCC) tumor cells, including cancer stem cells (CSC) that also coexpressed NKG2D. Moreover, tumor-infiltrating leukocytes (TIL), but not peripheral blood lymphoid cells (PBL) from ccRCC patients, over-expressed MICA, ULBP3 and ULBP4. In addition, NKG2D was downregulated on peripheral blood NK cells (PBNK) from ccRCC patients but upregulated on tumor-infiltrating NK cells (TINK). These TINK exhibited impaired degranulation that negatively correlated with NKG2D expression, diminished IFN-γ production, upregulation of TIM-3, and an impaired glucose intake upon stimulation with cytokines, indicating that they are dysfunctional, display features of exhaustion and an altered metabolic fitness. We conclude that ccRCC patients exhibit a distorted MICA-NKG2D axis, and MICA emerges as the forefront NKG2DL for the development of targeted therapies in ccRCC. |
| first_indexed | 2024-04-11T21:37:18Z |
| format | Article |
| id | doaj.art-1adb248fdaf140c9b28258767763461f |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-04-11T21:37:18Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-1adb248fdaf140c9b28258767763461f2022-12-22T04:01:42ZengTaylor & Francis GroupOncoImmunology2162-402X2022-12-0111110.1080/2162402X.2022.2104991The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncologyFlorencia Secchiari0Sol Yanel Nuñez1Jessica Mariel Sierra2Andrea Ziblat3María Victoria Regge4Ximena Lucía Raffo Iraolagoitia5Agustín Rovegno6Carlos Ameri7Fernando Pablo Secin8Nicolás Richards9Hernando Ríos Pita10Gonzalo Vitagliano11Luis Rico12Mauro Mieggi13Florencia Frascheri14Nicolás Bonanno15Leandro Blas16Aldana Trotta17Adrián David Friedrich18Mercedes Beatriz Fuertes19Carolina Inés Domaica20Norberto Walter Zwirner21Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaServicio de Urología, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC)Servicio de Urología, Hospital Alemán, Buenos Aires, ArgentinaServicio de Urología, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC)Servicio de Urología, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC)Servicio de Urología, Hospital Alemán, Buenos Aires, ArgentinaServicio de Urología, Hospital Alemán, Buenos Aires, ArgentinaServicio de Urología, Hospital Alemán, Buenos Aires, ArgentinaServicio de Urología, Hospital Alemán, Buenos Aires, ArgentinaServicio de Urología, Hospital Alemán, Buenos Aires, ArgentinaServicio de Urología, Hospital Alemán, Buenos Aires, ArgentinaServicio de Urología, Hospital Alemán, Buenos Aires, ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), ArgentinaNKG2D is a major natural killer (NK) cell-activating receptor that recognizes eight ligands (NKG2DLs), including MICA, and whose engagement triggers NK cell effector functions. As NKG2DLs are upregulated on tumor cells but tumors can subvert the NKG2D-NKG2DL axis, NKG2DLs constitute attractive targets for antibody (Ab)-based immuno-oncology therapies. However, such approaches require a deep characterization of NKG2DLs and NKG2D cell surface expression on primary tumor and immune cells. Here, using a bioinformatic analysis, we observed that MICA is overexpressed in renal cell carcinoma (RCC), and we also detected an association between the NKG2D-MICA axis and a diminished overall survival of RCC patients. Also, by flow cytometry (FC), we observed that MICA was the only NKG2DL over-expressed on clear cell renal cell carcinoma (ccRCC) tumor cells, including cancer stem cells (CSC) that also coexpressed NKG2D. Moreover, tumor-infiltrating leukocytes (TIL), but not peripheral blood lymphoid cells (PBL) from ccRCC patients, over-expressed MICA, ULBP3 and ULBP4. In addition, NKG2D was downregulated on peripheral blood NK cells (PBNK) from ccRCC patients but upregulated on tumor-infiltrating NK cells (TINK). These TINK exhibited impaired degranulation that negatively correlated with NKG2D expression, diminished IFN-γ production, upregulation of TIM-3, and an impaired glucose intake upon stimulation with cytokines, indicating that they are dysfunctional, display features of exhaustion and an altered metabolic fitness. We conclude that ccRCC patients exhibit a distorted MICA-NKG2D axis, and MICA emerges as the forefront NKG2DL for the development of targeted therapies in ccRCC.https://www.tandfonline.com/doi/10.1080/2162402X.2022.2104991NK cellsclear cell renal cell carcinomaNKG2DNKG2D ligandsMICAflow cytometry |
| spellingShingle | Florencia Secchiari Sol Yanel Nuñez Jessica Mariel Sierra Andrea Ziblat María Victoria Regge Ximena Lucía Raffo Iraolagoitia Agustín Rovegno Carlos Ameri Fernando Pablo Secin Nicolás Richards Hernando Ríos Pita Gonzalo Vitagliano Luis Rico Mauro Mieggi Florencia Frascheri Nicolás Bonanno Leandro Blas Aldana Trotta Adrián David Friedrich Mercedes Beatriz Fuertes Carolina Inés Domaica Norberto Walter Zwirner The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology OncoImmunology NK cells clear cell renal cell carcinoma NKG2D NKG2D ligands MICA flow cytometry |
| title | The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology |
| title_full | The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology |
| title_fullStr | The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology |
| title_full_unstemmed | The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology |
| title_short | The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology |
| title_sort | mica nkg2d axis in clear cell renal cell carcinoma bolsters mica as target in immuno oncology |
| topic | NK cells clear cell renal cell carcinoma NKG2D NKG2D ligands MICA flow cytometry |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2104991 |
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