A Dysfunctional T-cell Gene Signature for Predicting Nonresponse to PD-1 Blockade in Non-small Cell Lung Cancer That Is Suitable for Routine Clinical Diagnostics
©2023 The Authors; Published by the American Association for Cancer Research..
PURPOSE: Because PD-1 blockade is only effective in a minority of patients with advanced-stage non-small cell lung cancer (NSCLC), biomarkers are needed to guide treatment decisions. Tumor infiltration by PD-1T tumor-infiltrating lymphocytes (TIL), a dysfunctional TIL pool with tumor-reactive capacity, can be detected by digital quantitative IHC and has been established as a novel predictive biomarker in NSCLC. To facilitate translation of this biomarker to the clinic, we aimed to develop a robust RNA signature reflecting a tumor's PD-1T TIL status.
EXPERIMENTAL DESIGN: mRNA expression analysis using the NanoString nCounter platform was performed in baseline tumor samples from 41 patients with advanced-stage NSCLC treated with nivolumab that were selected on the basis of PD-1T TIL infiltration by IHC. Samples were included as a training cohort (n = 41) to develop a predictive gene signature. This signature was independently validated in a second cohort (n = 42). Primary outcome was disease control at 12 months (DC 12 m), and secondary outcome was progression-free and overall survival.
RESULTS: Regularized regression analysis yielded a signature using 12 out of 56 differentially expressed genes between PD-1T IHC-high tumors from patients with DC 12 m and PD-1T IHC-low tumors from patients with progressive disease (PD). In the validation cohort, 6/6 (100%) patients with DC 12 m and 23/36 (64%) with PD were correctly classified with a negative predictive value (NPV) of 100% and a positive predictive value of 32%.
CONCLUSIONS: The PD-1T mRNA signature showed a similar high sensitivity and high NPV as the digital IHC quantification of PD-1T TIL. This finding provides a straightforward approach allowing for easy implementation in a routine diagnostic clinical setting.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 30(2024), 4 vom: 16. Feb., Seite 814-823 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hummelink, Karlijn [VerfasserIn] |
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| Links: |
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| Themen: |
B7-H1 Antigen |
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| Anmerkungen: |
Date Completed 19.02.2024 Date Revised 14.03.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-23-1061 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM365796239 |
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| 100 | 1 | |a Hummelink, Karlijn |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Dysfunctional T-cell Gene Signature for Predicting Nonresponse to PD-1 Blockade in Non-small Cell Lung Cancer That Is Suitable for Routine Clinical Diagnostics |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2023 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a PURPOSE: Because PD-1 blockade is only effective in a minority of patients with advanced-stage non-small cell lung cancer (NSCLC), biomarkers are needed to guide treatment decisions. Tumor infiltration by PD-1T tumor-infiltrating lymphocytes (TIL), a dysfunctional TIL pool with tumor-reactive capacity, can be detected by digital quantitative IHC and has been established as a novel predictive biomarker in NSCLC. To facilitate translation of this biomarker to the clinic, we aimed to develop a robust RNA signature reflecting a tumor's PD-1T TIL status | ||
| 520 | |a EXPERIMENTAL DESIGN: mRNA expression analysis using the NanoString nCounter platform was performed in baseline tumor samples from 41 patients with advanced-stage NSCLC treated with nivolumab that were selected on the basis of PD-1T TIL infiltration by IHC. Samples were included as a training cohort (n = 41) to develop a predictive gene signature. This signature was independently validated in a second cohort (n = 42). Primary outcome was disease control at 12 months (DC 12 m), and secondary outcome was progression-free and overall survival | ||
| 520 | |a RESULTS: Regularized regression analysis yielded a signature using 12 out of 56 differentially expressed genes between PD-1T IHC-high tumors from patients with DC 12 m and PD-1T IHC-low tumors from patients with progressive disease (PD). In the validation cohort, 6/6 (100%) patients with DC 12 m and 23/36 (64%) with PD were correctly classified with a negative predictive value (NPV) of 100% and a positive predictive value of 32% | ||
| 520 | |a CONCLUSIONS: The PD-1T mRNA signature showed a similar high sensitivity and high NPV as the digital IHC quantification of PD-1T TIL. This finding provides a straightforward approach allowing for easy implementation in a routine diagnostic clinical setting | ||
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| 700 | 1 | |a Krijgsman, Oscar |e verfasserin |4 aut | |
| 700 | 1 | |a van den Heuvel, Michel M |e verfasserin |4 aut | |
| 700 | 1 | |a Theelen, Willemijn S M E |e verfasserin |4 aut | |
| 700 | 1 | |a Damotte, Diane |e verfasserin |4 aut | |
| 700 | 1 | |a Goldwasser, François |e verfasserin |4 aut | |
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| 700 | 1 | |a Monkhorst, Kim |e verfasserin |4 aut | |
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