Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype
Abstract Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients sho...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40745-5 |
| _version_ | 1827709565495410688 |
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| author | Stefanie Hiltbrunner Lena Cords Sabrina Kasser Sandra N. Freiberger Susanne Kreutzer Nora C. Toussaint Linda Grob Isabelle Opitz Michael Messerli Martin Zoche Alex Soltermann Markus Rechsteiner Maries van den Broek Bernd Bodenmiller Alessandra Curioni-Fontecedro |
| author_facet | Stefanie Hiltbrunner Lena Cords Sabrina Kasser Sandra N. Freiberger Susanne Kreutzer Nora C. Toussaint Linda Grob Isabelle Opitz Michael Messerli Martin Zoche Alex Soltermann Markus Rechsteiner Maries van den Broek Bernd Bodenmiller Alessandra Curioni-Fontecedro |
| author_sort | Stefanie Hiltbrunner |
| collection | DOAJ |
| description | Abstract Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8+ T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC. |
| first_indexed | 2024-03-10T17:23:44Z |
| format | Article |
| id | doaj.art-c99e4e76f6b544649dae1c58e4b5b5c4 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:23:44Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-c99e4e76f6b544649dae1c58e4b5b5c42023-11-20T10:16:05ZengNature PortfolioNature Communications2041-17232023-08-0114111410.1038/s41467-023-40745-5Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotypeStefanie Hiltbrunner0Lena Cords1Sabrina Kasser2Sandra N. Freiberger3Susanne Kreutzer4Nora C. Toussaint5Linda Grob6Isabelle Opitz7Michael Messerli8Martin Zoche9Alex Soltermann10Markus Rechsteiner11Maries van den Broek12Bernd Bodenmiller13Alessandra Curioni-Fontecedro14Department of Medical Oncology and Hematology, University Hospital ZurichUniversity of ZurichDepartment of Medical Oncology and Hematology, University Hospital ZurichDepartment of Pathology and Molecular Pathology, University Hospital ZurichFunctional Genomics Center Zurich, ETH and University of ZurichNEXUS Personalized Health Technologies, ETH ZurichNEXUS Personalized Health Technologies, ETH ZurichDepartment of Thoracic Surgery, University Hospital ZurichUniversity of ZurichDepartment of Pathology and Molecular Pathology, University Hospital ZurichDepartment of Pathology and Molecular Pathology, University Hospital ZurichDepartment of Pathology and Molecular Pathology, University Hospital ZurichUniversity of ZurichUniversity of ZurichDepartment of Medical Oncology and Hematology, University Hospital ZurichAbstract Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8+ T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC.https://doi.org/10.1038/s41467-023-40745-5 |
| spellingShingle | Stefanie Hiltbrunner Lena Cords Sabrina Kasser Sandra N. Freiberger Susanne Kreutzer Nora C. Toussaint Linda Grob Isabelle Opitz Michael Messerli Martin Zoche Alex Soltermann Markus Rechsteiner Maries van den Broek Bernd Bodenmiller Alessandra Curioni-Fontecedro Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype Nature Communications |
| title | Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype |
| title_full | Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype |
| title_fullStr | Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype |
| title_full_unstemmed | Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype |
| title_short | Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype |
| title_sort | acquired resistance to anti pd1 therapy in patients with nsclc associates with immunosuppressive t cell phenotype |
| url | https://doi.org/10.1038/s41467-023-40745-5 |
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