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BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study

Clear cell renal cell carcinoma (ccRCC) is an immunologically vulnerable tumor entity, and immune checkpoint inhibitors are now widely used to treat patients with advanced disease. Whether and to what extent immune responses in ccRCC are shaped by genetic alterations, however, is only beginning to e...

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Autores principales: Friedhoff, Jana, Schneider, Felix, Jurcic, Christina, Endris, Volker, Kirchner, Martina, Sun, Angela, Bolnavu, Iulia, Pohl, Laura, Teroerde, Miriam, Kippenberger, Maximilian, Schwab, Constantin, Kaczorowski, Adam, Zschäbitz, Stefanie, Jäger, Dirk, Hohenfellner, Markus, Stenzinger, Albrecht, Duensing, Anette, Duensing, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198938/
https://www.ncbi.nlm.nih.gov/pubmed/36562826
http://dx.doi.org/10.1007/s00262-022-03346-7
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author Friedhoff, Jana
Schneider, Felix
Jurcic, Christina
Endris, Volker
Kirchner, Martina
Sun, Angela
Bolnavu, Iulia
Pohl, Laura
Teroerde, Miriam
Kippenberger, Maximilian
Schwab, Constantin
Kaczorowski, Adam
Zschäbitz, Stefanie
Jäger, Dirk
Hohenfellner, Markus
Stenzinger, Albrecht
Duensing, Anette
Duensing, Stefan
author_facet Friedhoff, Jana
Schneider, Felix
Jurcic, Christina
Endris, Volker
Kirchner, Martina
Sun, Angela
Bolnavu, Iulia
Pohl, Laura
Teroerde, Miriam
Kippenberger, Maximilian
Schwab, Constantin
Kaczorowski, Adam
Zschäbitz, Stefanie
Jäger, Dirk
Hohenfellner, Markus
Stenzinger, Albrecht
Duensing, Anette
Duensing, Stefan
author_sort Friedhoff, Jana
collection PubMed
description Clear cell renal cell carcinoma (ccRCC) is an immunologically vulnerable tumor entity, and immune checkpoint inhibitors are now widely used to treat patients with advanced disease. Whether and to what extent immune responses in ccRCC are shaped by genetic alterations, however, is only beginning to emerge. In this proof-of-concept study, we performed a detailed correlative analysis of the mutational and immunological landscapes in a series of 23 consecutive kidney cancer patients. We discovered that a high infiltration with CD8 + T cells was not dependent on the number of driver mutations but rather on the presence of specific mutational events, namely pathogenic mutations in PTEN or BAP1. This observation encouraged us to compare mechanisms of T cell suppression in the context of four different genetic patterns, i.e., the presence of multiple drivers, a PTEN or BAP1 mutation, or the absence of detectable driver mutations. We found that ccRCCs harboring a PTEN or BAP1 mutation showed the lowest level of Granzyme B positive tumor-infiltrating lymphocytes (TILs). A multiplex immunofluorescence analysis revealed a significant number of CD8 + TILs in the vicinity of CD68 + macrophages/monocytes in the context of a BAP1 mutation but not in the context of a PTEN mutation. In line with this finding, direct interactions between CD8 + TILs and CD163 + M2-polarized macrophages were found in BAP1-mutated ccRCC but not in tumors with other mutational patterns. While an absence of driver mutations was associated with more CD8 + TILs in the vicinity of FOXP3 + Tregs and CD68 + monocytes/macrophages, the presence of multiple driver mutations was, to our surprise, not found to be strongly associated with immunosuppressive mechanisms. Our results highlight the role of genetic alterations in shaping the immunological landscape of ccRCC. We discovered a remarkable heterogeneity of mechanisms that can lead to T cell suppression, which supports the need for personalized immune oncological approaches.
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spelling pubmed-101989382023-05-21 BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study Friedhoff, Jana Schneider, Felix Jurcic, Christina Endris, Volker Kirchner, Martina Sun, Angela Bolnavu, Iulia Pohl, Laura Teroerde, Miriam Kippenberger, Maximilian Schwab, Constantin Kaczorowski, Adam Zschäbitz, Stefanie Jäger, Dirk Hohenfellner, Markus Stenzinger, Albrecht Duensing, Anette Duensing, Stefan Cancer Immunol Immunother Research Clear cell renal cell carcinoma (ccRCC) is an immunologically vulnerable tumor entity, and immune checkpoint inhibitors are now widely used to treat patients with advanced disease. Whether and to what extent immune responses in ccRCC are shaped by genetic alterations, however, is only beginning to emerge. In this proof-of-concept study, we performed a detailed correlative analysis of the mutational and immunological landscapes in a series of 23 consecutive kidney cancer patients. We discovered that a high infiltration with CD8 + T cells was not dependent on the number of driver mutations but rather on the presence of specific mutational events, namely pathogenic mutations in PTEN or BAP1. This observation encouraged us to compare mechanisms of T cell suppression in the context of four different genetic patterns, i.e., the presence of multiple drivers, a PTEN or BAP1 mutation, or the absence of detectable driver mutations. We found that ccRCCs harboring a PTEN or BAP1 mutation showed the lowest level of Granzyme B positive tumor-infiltrating lymphocytes (TILs). A multiplex immunofluorescence analysis revealed a significant number of CD8 + TILs in the vicinity of CD68 + macrophages/monocytes in the context of a BAP1 mutation but not in the context of a PTEN mutation. In line with this finding, direct interactions between CD8 + TILs and CD163 + M2-polarized macrophages were found in BAP1-mutated ccRCC but not in tumors with other mutational patterns. While an absence of driver mutations was associated with more CD8 + TILs in the vicinity of FOXP3 + Tregs and CD68 + monocytes/macrophages, the presence of multiple driver mutations was, to our surprise, not found to be strongly associated with immunosuppressive mechanisms. Our results highlight the role of genetic alterations in shaping the immunological landscape of ccRCC. We discovered a remarkable heterogeneity of mechanisms that can lead to T cell suppression, which supports the need for personalized immune oncological approaches. Springer Berlin Heidelberg 2022-12-23 2023 /pmc/articles/PMC10198938/ /pubmed/36562826 http://dx.doi.org/10.1007/s00262-022-03346-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research
Friedhoff, Jana
Schneider, Felix
Jurcic, Christina
Endris, Volker
Kirchner, Martina
Sun, Angela
Bolnavu, Iulia
Pohl, Laura
Teroerde, Miriam
Kippenberger, Maximilian
Schwab, Constantin
Kaczorowski, Adam
Zschäbitz, Stefanie
Jäger, Dirk
Hohenfellner, Markus
Stenzinger, Albrecht
Duensing, Anette
Duensing, Stefan
BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study
title BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study
title_full BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study
title_fullStr BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study
title_full_unstemmed BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study
title_short BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study
title_sort bap1 and pten mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of t cell suppression: a proof-of-concept study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198938/
https://www.ncbi.nlm.nih.gov/pubmed/36562826
http://dx.doi.org/10.1007/s00262-022-03346-7
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