Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials
Background The immune status of a patient’s tumor microenvironment (TME) may guide therapeutic interventions with cancer immunotherapy and help identify potential resistance mechanisms. Currently, patients’ immune status is mostly classified based on CD8+tumor-infiltrating lymphocytes. An unmet need...
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BMJ Publishing Group
2024-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/4/e008185.full |
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| author | Cláudia S Ferreira Konstanty Korski Michael A Cannarile Irina Klaman Petra C Schwalie Iakov I Davydov Andreas Roller Martha L Serrano-Serrano Astrid Heller Nicolas Staedler Gabriele Dietmann Alberto Valdeolivas |
| author_facet | Cláudia S Ferreira Konstanty Korski Michael A Cannarile Irina Klaman Petra C Schwalie Iakov I Davydov Andreas Roller Martha L Serrano-Serrano Astrid Heller Nicolas Staedler Gabriele Dietmann Alberto Valdeolivas |
| author_sort | Cláudia S Ferreira |
| collection | DOAJ |
| description | Background The immune status of a patient’s tumor microenvironment (TME) may guide therapeutic interventions with cancer immunotherapy and help identify potential resistance mechanisms. Currently, patients’ immune status is mostly classified based on CD8+tumor-infiltrating lymphocytes. An unmet need exists for comparable and reliable precision immunophenotyping tools that would facilitate clinical treatment-relevant decision-making and the understanding of how to overcome resistance mechanisms.Methods We systematically analyzed the CD8 immunophenotype of 2023 patients from 14 phase I–III clinical trials using immunohistochemistry (IHC) and additionally profiled gene expression by RNA-sequencing (RNA-seq). CD8 immunophenotypes were classified by pathologists into CD8-desert, CD8-excluded or CD8-inflamed tumors using CD8 IHC staining in epithelial and stromal areas of the tumor. Using regularized logistic regression, we developed an RNA-seq-based classifier as a surrogate to the IHC-based spatial classification of CD8+tumor-infiltrating lymphocytes in the TME.Results The CD8 immunophenotype and associated gene expression patterns varied across indications as well as across primary and metastatic lesions. Melanoma and kidney cancers were among the strongest inflamed indications, while CD8-desert phenotypes were most abundant in liver metastases across all tumor types. A good correspondence between the transcriptome and the IHC-based evaluation enabled us to develop a 92-gene classifier that accurately predicted the IHC-based CD8 immunophenotype in primary and metastatic samples (area under the curve inflamed=0.846; excluded=0.712; desert=0.855). The newly developed classifier was prognostic in The Cancer Genome Atlas (TCGA) data and predictive in lung cancer: patients with predicted CD8-inflamed tumors showed prolonged overall survival (OS) versus patients with CD8-desert tumors (HR 0.88; 95% CI 0.80 to 0.97) across TCGA, and longer OS on immune checkpoint inhibitor administration (phase III OAK study) in non-small-cell lung cancer (HR 0.75; 95% CI 0.58 to 0.97).Conclusions We provide a new precision immunophenotyping tool based on gene expression that reflects the spatial infiltration patterns of CD8+ lymphocytes in tumors. The classifier enables multiplex analyses and is easy to apply for retrospective, reverse translation approaches as well as for prospective patient enrichment to optimize the response to cancer immunotherapy. |
| format | Article |
| id | doaj-art-a65b392cfd034dc18fbbd68b9a6b32bf |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-a65b392cfd034dc18fbbd68b9a6b32bf2024-11-14T03:50:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-04-0112410.1136/jitc-2023-008185Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trialsCláudia S Ferreira0Konstanty Korski1Michael A Cannarile2Irina Klaman3Petra C Schwalie4Iakov I Davydov5Andreas Roller6Martha L Serrano-Serrano7Astrid Heller8Nicolas Staedler9Gabriele Dietmann10Alberto Valdeolivas11Roche Pharma Research and Early Development, Early Development Oncology, Roche Innovation Center, Roche Diagnostics GmbH, Munich, GermanyRoche Product Development, PHC Data, Analytics and Imaging, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandRoche Pharma Research and Early Development, Early Development Oncology, Roche Innovation Center, Roche Diagnostics GmbH, Munich, GermanyRoche Pharma Research and Early Development, Early Development Oncology, Roche Innovation Center, Roche Diagnostics GmbH, Munich, GermanyRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandRoche Pharma Research and Early Development, Early Development Oncology, Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandRoche Pharma Research and Early Development, Early Development Oncology, Roche Innovation Center, Roche Diagnostics GmbH, Munich, GermanyRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandRoche Pharma Research and Early Development, Early Development Oncology, Roche Innovation Center, Roche Diagnostics GmbH, Munich, GermanyRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandBackground The immune status of a patient’s tumor microenvironment (TME) may guide therapeutic interventions with cancer immunotherapy and help identify potential resistance mechanisms. Currently, patients’ immune status is mostly classified based on CD8+tumor-infiltrating lymphocytes. An unmet need exists for comparable and reliable precision immunophenotyping tools that would facilitate clinical treatment-relevant decision-making and the understanding of how to overcome resistance mechanisms.Methods We systematically analyzed the CD8 immunophenotype of 2023 patients from 14 phase I–III clinical trials using immunohistochemistry (IHC) and additionally profiled gene expression by RNA-sequencing (RNA-seq). CD8 immunophenotypes were classified by pathologists into CD8-desert, CD8-excluded or CD8-inflamed tumors using CD8 IHC staining in epithelial and stromal areas of the tumor. Using regularized logistic regression, we developed an RNA-seq-based classifier as a surrogate to the IHC-based spatial classification of CD8+tumor-infiltrating lymphocytes in the TME.Results The CD8 immunophenotype and associated gene expression patterns varied across indications as well as across primary and metastatic lesions. Melanoma and kidney cancers were among the strongest inflamed indications, while CD8-desert phenotypes were most abundant in liver metastases across all tumor types. A good correspondence between the transcriptome and the IHC-based evaluation enabled us to develop a 92-gene classifier that accurately predicted the IHC-based CD8 immunophenotype in primary and metastatic samples (area under the curve inflamed=0.846; excluded=0.712; desert=0.855). The newly developed classifier was prognostic in The Cancer Genome Atlas (TCGA) data and predictive in lung cancer: patients with predicted CD8-inflamed tumors showed prolonged overall survival (OS) versus patients with CD8-desert tumors (HR 0.88; 95% CI 0.80 to 0.97) across TCGA, and longer OS on immune checkpoint inhibitor administration (phase III OAK study) in non-small-cell lung cancer (HR 0.75; 95% CI 0.58 to 0.97).Conclusions We provide a new precision immunophenotyping tool based on gene expression that reflects the spatial infiltration patterns of CD8+ lymphocytes in tumors. The classifier enables multiplex analyses and is easy to apply for retrospective, reverse translation approaches as well as for prospective patient enrichment to optimize the response to cancer immunotherapy.https://jitc.bmj.com/content/12/4/e008185.full |
| spellingShingle | Cláudia S Ferreira Konstanty Korski Michael A Cannarile Irina Klaman Petra C Schwalie Iakov I Davydov Andreas Roller Martha L Serrano-Serrano Astrid Heller Nicolas Staedler Gabriele Dietmann Alberto Valdeolivas Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials Journal for ImmunoTherapy of Cancer |
| title | Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials |
| title_full | Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials |
| title_fullStr | Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials |
| title_full_unstemmed | Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials |
| title_short | Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials |
| title_sort | tumor agnostic transcriptome based classifier identifies spatial infiltration patterns of cd8 t cells in the tumor microenvironment and predicts clinical outcome in early phase and late phase clinical trials |
| url | https://jitc.bmj.com/content/12/4/e008185.full |
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