Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer
Background Napsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We used bulk T-cell receptor (TCR) repertoir...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-07-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/7/e011907.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849319129096388608 |
|---|---|
| author | Crystal Mackall Heather Wakelee Sylvia Lee Keith D Eaton Cristina Rodriguez Rafael Santana-Davila Joel W Neal Natalie J Miller Elena Sotillo Tatyana Pisarenko Eric Q Konnick Christina Baik Fangdi Sun Renato G Martins Sukhmani K Padda Alex Camai Viswam S Nair A McGarry Houghton Shin-Heng Chiou Diane Tseng |
| author_facet | Crystal Mackall Heather Wakelee Sylvia Lee Keith D Eaton Cristina Rodriguez Rafael Santana-Davila Joel W Neal Natalie J Miller Elena Sotillo Tatyana Pisarenko Eric Q Konnick Christina Baik Fangdi Sun Renato G Martins Sukhmani K Padda Alex Camai Viswam S Nair A McGarry Houghton Shin-Heng Chiou Diane Tseng |
| author_sort | Crystal Mackall |
| collection | DOAJ |
| description | Background Napsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We used bulk T-cell receptor (TCR) repertoire data to assess whether the presence of Napsin A-specific clonotypes in the peripheral blood was associated with improved clinical responses to ICI.Methods Patients with metastatic non-small cell lung cancer (NSCLC) receiving anti-programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n=62; histology of adenocarcinoma n=48, squamous n=9, NSCLC/other n=5). Peripheral blood mononuclear cells were collected for genomic DNA isolation at one pretreatment and one post-treatment time point (range 3 weeks to 3 months). TCRβ was bulk sequenced via the immunoSEQ platform (Adaptive Biotechnologies). Napsin A-specific TCRβ sequences were identified from publicly available data and their frequencies were quantified in each patient sample. We examined whether overall survival (OS) and progression-free survival (PFS) outcomes differed in patients with or without detectable Napsin A-specific TCRs (herein Napsin TCRs). We used Cox proportional hazards regression to assess the association between detectable Napsin TCRs and PFS or OS in univariable and multivariable analyses.Results Napsin TCRs were detectable in the blood in a large fraction of our cohort (n=25/62 (40%) pretreatment; n=21/42 (50%) post-treatment). Patients with detectable Napsin TCRs had a significant improvement in OS compared with patients without these TCRs (median OS 45.4 vs 14.8 months, p=0.0043 pretreatment; median OS 55.4 vs 18.9 months, p=0.0066 post-treatment). Among 27 HLA-A*02 carriers of 55 human leukocyte antigen-typed patients (49%), patients with detectable pretreatment Napsin TCRs had a significant improvement in OS (median 60.2 vs 16.5 months, p=0.0054) and PFS (median 21.5 vs 7.2 months, p=0.031) compared with patients without these TCRs. In univariate and multivariate analysis, the presence of Napsin TCRs pretreatment was associated with improved OS (p=0.0057, HR 0.40, 95% CI 0.21 to 0.76 univariate; p=0.033, HR 0.45, 95% CI 0.23 to 0.91 multivariate).Conclusions Napsin TCRs are frequently detected in patients with NSCLC and are associated with improved OS in patients with NSCLC receiving ICI. |
| format | Article |
| id | doaj-art-d2c45fe7eb2c4d87a2ba7aac15c35146 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d2c45fe7eb2c4d87a2ba7aac15c351462025-08-20T03:50:38ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-07-0113710.1136/jitc-2025-011907Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancerCrystal Mackall0Heather Wakelee1Sylvia Lee2Keith D Eaton3Cristina Rodriguez4Rafael Santana-Davila5Joel W Neal6Natalie J Miller7Elena Sotillo8Tatyana Pisarenko9Eric Q Konnick10Christina Baik11Fangdi Sun12Renato G Martins13Sukhmani K Padda14Alex Camai15Viswam S Nair16A McGarry Houghton17Shin-Heng Chiou18Diane Tseng197 Medicine and Pediatrics, Stanford University, Stanford, California, USA3 Department of Medicine, Stanford University, Stanford, California, USA1 University of Washington, Seattle, Washington, USA1 University of Washington, Seattle, Washington, USA1 University of Washington, Seattle, Washington, USA1 University of Washington, Seattle, Washington, USA3 Department of Medicine, Stanford University, Stanford, California, USA1 University of Washington, Seattle, Washington, USA6 Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, California, USA2 Fred Hutchinson Cancer Center, Seattle, Washington, USA1 University of Washington, Seattle, Washington, USA1 University of Washington, Seattle, Washington, USA3 Department of Medicine, Stanford University, Stanford, California, USA4 Virginia Commonwealth University, Richmond, Virginia, USA5 Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA2 Fred Hutchinson Cancer Center, Seattle, Washington, USA1 University of Washington, Seattle, Washington, USA1 University of Washington, Seattle, Washington, USA8 Medicine, Rutgers Cancer Institute, New Brunswick, New Jersey, USA1 University of Washington, Seattle, Washington, USABackground Napsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We used bulk T-cell receptor (TCR) repertoire data to assess whether the presence of Napsin A-specific clonotypes in the peripheral blood was associated with improved clinical responses to ICI.Methods Patients with metastatic non-small cell lung cancer (NSCLC) receiving anti-programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n=62; histology of adenocarcinoma n=48, squamous n=9, NSCLC/other n=5). Peripheral blood mononuclear cells were collected for genomic DNA isolation at one pretreatment and one post-treatment time point (range 3 weeks to 3 months). TCRβ was bulk sequenced via the immunoSEQ platform (Adaptive Biotechnologies). Napsin A-specific TCRβ sequences were identified from publicly available data and their frequencies were quantified in each patient sample. We examined whether overall survival (OS) and progression-free survival (PFS) outcomes differed in patients with or without detectable Napsin A-specific TCRs (herein Napsin TCRs). We used Cox proportional hazards regression to assess the association between detectable Napsin TCRs and PFS or OS in univariable and multivariable analyses.Results Napsin TCRs were detectable in the blood in a large fraction of our cohort (n=25/62 (40%) pretreatment; n=21/42 (50%) post-treatment). Patients with detectable Napsin TCRs had a significant improvement in OS compared with patients without these TCRs (median OS 45.4 vs 14.8 months, p=0.0043 pretreatment; median OS 55.4 vs 18.9 months, p=0.0066 post-treatment). Among 27 HLA-A*02 carriers of 55 human leukocyte antigen-typed patients (49%), patients with detectable pretreatment Napsin TCRs had a significant improvement in OS (median 60.2 vs 16.5 months, p=0.0054) and PFS (median 21.5 vs 7.2 months, p=0.031) compared with patients without these TCRs. In univariate and multivariate analysis, the presence of Napsin TCRs pretreatment was associated with improved OS (p=0.0057, HR 0.40, 95% CI 0.21 to 0.76 univariate; p=0.033, HR 0.45, 95% CI 0.23 to 0.91 multivariate).Conclusions Napsin TCRs are frequently detected in patients with NSCLC and are associated with improved OS in patients with NSCLC receiving ICI.https://jitc.bmj.com/content/13/7/e011907.full |
| spellingShingle | Crystal Mackall Heather Wakelee Sylvia Lee Keith D Eaton Cristina Rodriguez Rafael Santana-Davila Joel W Neal Natalie J Miller Elena Sotillo Tatyana Pisarenko Eric Q Konnick Christina Baik Fangdi Sun Renato G Martins Sukhmani K Padda Alex Camai Viswam S Nair A McGarry Houghton Shin-Heng Chiou Diane Tseng Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer Journal for ImmunoTherapy of Cancer |
| title | Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer |
| title_full | Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer |
| title_fullStr | Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer |
| title_full_unstemmed | Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer |
| title_short | Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer |
| title_sort | napsin a specific t cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non small cell lung cancer |
| url | https://jitc.bmj.com/content/13/7/e011907.full |
| work_keys_str_mv | AT crystalmackall napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT heatherwakelee napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT sylvialee napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT keithdeaton napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT cristinarodriguez napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT rafaelsantanadavila napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT joelwneal napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT nataliejmiller napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT elenasotillo napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT tatyanapisarenko napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT ericqkonnick napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT christinabaik napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT fangdisun napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT renatogmartins napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT sukhmanikpadda napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT alexcamai napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT viswamsnair napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT amcgarryhoughton napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT shinhengchiou napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer AT dianetseng napsinaspecifictcellclonotypesareassociatedwithimprovedclinicaloutcomesinpatientsreceivingcheckpointimmunotherapyformetastaticnonsmallcelllungcancer |