Impact of age‐related T‐cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: A prospective cohort study
Abstract Background The impact of biologic aging on immune checkpoint inhibitor (ICI) toxicity and efficacy is underexplored in metastatic melanoma (MM). In peripheral blood T lymphocytes (PBTLs), biologic aging is characterized by changes in T‐cell composition and cellular senescence. Whether indic...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-12-01
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| Series: | Aging and Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/aac2.12012 |
| _version_ | 1818905500283043840 |
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| author | Jason E. Galloway Andrea M. Holderbaum Namrata Arya Suohui Zhang Michael S. Bodnar Ruthann Norman William E. Carson Lianbo Yu Kari L. Kendra Christin E. Burd |
| author_facet | Jason E. Galloway Andrea M. Holderbaum Namrata Arya Suohui Zhang Michael S. Bodnar Ruthann Norman William E. Carson Lianbo Yu Kari L. Kendra Christin E. Burd |
| author_sort | Jason E. Galloway |
| collection | DOAJ |
| description | Abstract Background The impact of biologic aging on immune checkpoint inhibitor (ICI) toxicity and efficacy is underexplored in metastatic melanoma (MM). In peripheral blood T lymphocytes (PBTLs), biologic aging is characterized by changes in T‐cell composition and cellular senescence. Whether indicators of PBTL biologic aging vary in MM patients or can be used to predict premature ICI discontinuation (pID) is unknown. Methods We prospectively collected PBTLs from 117 cancer‐free controls and 46 MM patients scheduled to begin pembrolizumab or nivolumab monotherapy. Seventy‐four mRNAs indicative of T‐cell subset, activation, costimulation/inhibition, and cellular senescence were measured by Nanostring. Relationships between each mRNA and chronologic age were assessed in patients and controls. Candidate biomarkers were identified by calculating the hazard ratio (HR) for pID in patients divided into low and high groups based on log‐transformed mRNA levels or the magnitude by which each mRNA measurement deviated from the control trend (Δage). Area under the curve (AUC) analyses explored the ability of each biomarker to discriminate between patients with and without pID at 6 months and 1 year. Results Fifteen mRNAs correlated with chronologic age in controls, including markers of T‐cell subset, differentiation, cytokine production, and costimulation/inhibition. None of these mRNAs remained correlated with age in patients. Median follow‐up was 94.8 (1.6‐195.7) weeks and 35 of 46 patients discontinued therapy (23 progression, seven toxicity, and five comorbidity/patient preference). Elevated pretherapy CD8A (HR = 2.2 [1.1‐4.9]), CD45RB (HR = 2.9 [1.4‐5.8]), and TNFRSF14 (HR = 2.2 [1.1‐4.5]) levels predicted pID independent of Δage‐correction. CD3ε, CD27, and FOXO1 predicted pID only after Δage‐correction (HR = 2.5 [1.3‐5.1]; 3.7 [1.8‐7.8]; 2.1 [1.1‐4.3]). AUC analysis identified Δage‐CD3ε and Δage‐CD27 as candidate predictors of pID (AUC = .73 and .75). Conclusions Correlations between transcriptional markers of PBTL composition and chronologic age are disrupted in MM. Correcting for normal, age‐related trends in biomarker expression unveils new biomarker candidates predictive of ICI outcomes. |
| first_indexed | 2024-12-19T21:24:19Z |
| format | Article |
| id | doaj.art-2c40ae84ca684e13a38c61652404594d |
| institution | Directory Open Access Journal |
| issn | 2643-8909 |
| language | English |
| last_indexed | 2024-12-19T21:24:19Z |
| publishDate | 2020-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Aging and Cancer |
| spelling | doaj.art-2c40ae84ca684e13a38c61652404594d2022-12-21T20:05:10ZengWileyAging and Cancer2643-89092020-12-0111-4587010.1002/aac2.12012Impact of age‐related T‐cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: A prospective cohort studyJason E. Galloway0Andrea M. Holderbaum1Namrata Arya2Suohui Zhang3Michael S. Bodnar4Ruthann Norman5William E. Carson6Lianbo Yu7Kari L. Kendra8Christin E. Burd9Department of Molecular Genetics The Ohio State University College of Arts and Sciences Columbus OhioDepartment of Molecular Genetics The Ohio State University College of Arts and Sciences Columbus OhioDepartment of Molecular Genetics The Ohio State University College of Arts and Sciences Columbus OhioDepartment of Molecular Genetics The Ohio State University College of Arts and Sciences Columbus OhioDepartment of Molecular Genetics The Ohio State University College of Arts and Sciences Columbus OhioDivision of Surgical Oncology Department of Surgery The Ohio State University College of Medicine Columbus OhioDivision of Surgical Oncology Department of Surgery The Ohio State University College of Medicine Columbus OhioDepartment of Biomedical Informatics Center for Biostatistics The Ohio State University College of Medicine Columbus OhioMedical Oncology Division Department of Internal Medicine The Ohio State University College of Medicine Columbus OhioDepartment of Molecular Genetics The Ohio State University College of Arts and Sciences Columbus OhioAbstract Background The impact of biologic aging on immune checkpoint inhibitor (ICI) toxicity and efficacy is underexplored in metastatic melanoma (MM). In peripheral blood T lymphocytes (PBTLs), biologic aging is characterized by changes in T‐cell composition and cellular senescence. Whether indicators of PBTL biologic aging vary in MM patients or can be used to predict premature ICI discontinuation (pID) is unknown. Methods We prospectively collected PBTLs from 117 cancer‐free controls and 46 MM patients scheduled to begin pembrolizumab or nivolumab monotherapy. Seventy‐four mRNAs indicative of T‐cell subset, activation, costimulation/inhibition, and cellular senescence were measured by Nanostring. Relationships between each mRNA and chronologic age were assessed in patients and controls. Candidate biomarkers were identified by calculating the hazard ratio (HR) for pID in patients divided into low and high groups based on log‐transformed mRNA levels or the magnitude by which each mRNA measurement deviated from the control trend (Δage). Area under the curve (AUC) analyses explored the ability of each biomarker to discriminate between patients with and without pID at 6 months and 1 year. Results Fifteen mRNAs correlated with chronologic age in controls, including markers of T‐cell subset, differentiation, cytokine production, and costimulation/inhibition. None of these mRNAs remained correlated with age in patients. Median follow‐up was 94.8 (1.6‐195.7) weeks and 35 of 46 patients discontinued therapy (23 progression, seven toxicity, and five comorbidity/patient preference). Elevated pretherapy CD8A (HR = 2.2 [1.1‐4.9]), CD45RB (HR = 2.9 [1.4‐5.8]), and TNFRSF14 (HR = 2.2 [1.1‐4.5]) levels predicted pID independent of Δage‐correction. CD3ε, CD27, and FOXO1 predicted pID only after Δage‐correction (HR = 2.5 [1.3‐5.1]; 3.7 [1.8‐7.8]; 2.1 [1.1‐4.3]). AUC analysis identified Δage‐CD3ε and Δage‐CD27 as candidate predictors of pID (AUC = .73 and .75). Conclusions Correlations between transcriptional markers of PBTL composition and chronologic age are disrupted in MM. Correcting for normal, age‐related trends in biomarker expression unveils new biomarker candidates predictive of ICI outcomes.https://doi.org/10.1002/aac2.12012aging biomarkerCD27checkpoint inhibitormelanomasenescence |
| spellingShingle | Jason E. Galloway Andrea M. Holderbaum Namrata Arya Suohui Zhang Michael S. Bodnar Ruthann Norman William E. Carson Lianbo Yu Kari L. Kendra Christin E. Burd Impact of age‐related T‐cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: A prospective cohort study Aging and Cancer aging biomarker CD27 checkpoint inhibitor melanoma senescence |
| title | Impact of age‐related T‐cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: A prospective cohort study |
| title_full | Impact of age‐related T‐cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: A prospective cohort study |
| title_fullStr | Impact of age‐related T‐cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: A prospective cohort study |
| title_full_unstemmed | Impact of age‐related T‐cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: A prospective cohort study |
| title_short | Impact of age‐related T‐cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation: A prospective cohort study |
| title_sort | impact of age related t cell dynamics on the identification of biomarkers predictive of immunotherapy discontinuation a prospective cohort study |
| topic | aging biomarker CD27 checkpoint inhibitor melanoma senescence |
| url | https://doi.org/10.1002/aac2.12012 |
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