Gene-expression signature predicts autoimmune toxicity in metastatic melanoma
Objectives To identify predictive gene-expression signatures for immune-related adverse events (irAEs) in patients with melanoma treated with anti-PD-1 inhibitors, in the adjuvant therapy (AT) and first-line therapy (FLT).Methods This retrospective study analyzed baseline whole-blood gene expression...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2025-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/7/e011315.full |
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| author | Michael Bailey Andrew White Francesca Sparano Alessandra Cesano Mariaelena Capone Corrado Caracò Ester Simeone Lucia Festino Alfredo Budillon Sarah Warren Domenico Mallardo Paolo A Ascierto Vito Vanella Ernesta Cavalcanti Claudia Trojaniello Maria Grazia Vitale Margaret Ottaviano Paolo Chiodini Mario Fordellone Bianca Arianna Facchini Maria Ingenito Caterina Costa Rosaria De Filippi |
| author_facet | Michael Bailey Andrew White Francesca Sparano Alessandra Cesano Mariaelena Capone Corrado Caracò Ester Simeone Lucia Festino Alfredo Budillon Sarah Warren Domenico Mallardo Paolo A Ascierto Vito Vanella Ernesta Cavalcanti Claudia Trojaniello Maria Grazia Vitale Margaret Ottaviano Paolo Chiodini Mario Fordellone Bianca Arianna Facchini Maria Ingenito Caterina Costa Rosaria De Filippi |
| author_sort | Michael Bailey |
| collection | DOAJ |
| description | Objectives To identify predictive gene-expression signatures for immune-related adverse events (irAEs) in patients with melanoma treated with anti-PD-1 inhibitors, in the adjuvant therapy (AT) and first-line therapy (FLT).Methods This retrospective study analyzed baseline whole-blood gene expression profile from 161 patients with resected stage III or unresectable stage III-IV melanoma treated with anti-PD-1 inhibitors. RNA was extracted from baseline peripheral blood samples and profiled using the NanoString nCounter PanCancer IO 360 panel. Gene-expression signatures were identified and validated using cross-validated sparse partial least squares modeling and principal component analysis, then correlated with toxicity occurrence.Results A total of 223 and 186 irAEs were observed in the AT and FLT groups, respectively, including arthralgia, colitis, and headache. Distinct gene-expression signatures significantly predicted toxicity occurrence, with variation across therapy settings. Arthralgia was predicted by immune-related and apoptotic gene signatures (eg, SMAD5, FASLG in FLT; ICOS, TGFB2 in AT), while colitis was linked to inflammatory and adhesion-related pathways. In the AT group, headache was associated with genes involved in interferon and adhesion signaling. Across both cohorts, specific signatures predicted overall irAE risk and timing. No events were observed in patients with low-risk signatures over the follow-up period. In the FLT cohort, arthralgia and cutaneous toxicities were positively associated with ORR, while arthralgia, asthenia, colitis, fatigue, and skin-related toxicities correlated with improved disease control rate. No significant association between irAEs and relapse risk was observed in the adjuvant cohort.Conclusions Whole-blood gene-expression profiling enables early identification of patients at high risk for irAEs during anti-PD-1 therapy. These predictive biomarkers may guide personalized toxicity monitoring in melanoma treatment. |
| format | Article |
| id | doaj-art-6114ba91f90447c6b0ba1e862ffa2f09 |
| 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-6114ba91f90447c6b0ba1e862ffa2f092025-08-20T03:33:35ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-07-0113710.1136/jitc-2024-011315Gene-expression signature predicts autoimmune toxicity in metastatic melanomaMichael Bailey0Andrew White1Francesca Sparano2Alessandra Cesano3Mariaelena Capone4Corrado Caracò5Ester Simeone6Lucia Festino7Alfredo Budillon8Sarah Warren9Domenico Mallardo10Paolo A Ascierto11Vito Vanella12Ernesta Cavalcanti13Claudia Trojaniello14Maria Grazia Vitale15Margaret Ottaviano16Paolo Chiodini17Mario Fordellone18Bianca Arianna Facchini19Maria Ingenito20Caterina Costa21Rosaria De Filippi22Research and Development, NanoString Technologies Inc, Seattle, Washington, USAResearch and Development, NanoString Technologies Inc, Seattle, Washington, USAUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyESSA Pharma, South San Francisco, California, USAUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyDivision of Surgery of Melanoma and Skin Cancer, Istituto Nazionale Tumori – IRCCS – Fondazione `G. Pascale`, Naples, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyScientifc Directorate, Istituto Nazionale Tumori – IRCCS – Fondazione `G. Pascale`, Naples, ItalyESSA Pharma, South San Francisco, California, USAUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyDivision of Laboratory Medicine, Istituto Nazionale Tumori – IRCCS – Fondazione `G. Pascale`, Naples, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalySalute Mentale e Fisica e Medicina Preventiva, University of Campania Luigi Vanvitelli, Napoli, ItalySalute Mentale e Fisica e Medicina Preventiva, University of Campania Luigi Vanvitelli, Napoli, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, ItalyDepartment of Clinical Medicine and Surgery, University of Naples Federico II, Naples, ItalyObjectives To identify predictive gene-expression signatures for immune-related adverse events (irAEs) in patients with melanoma treated with anti-PD-1 inhibitors, in the adjuvant therapy (AT) and first-line therapy (FLT).Methods This retrospective study analyzed baseline whole-blood gene expression profile from 161 patients with resected stage III or unresectable stage III-IV melanoma treated with anti-PD-1 inhibitors. RNA was extracted from baseline peripheral blood samples and profiled using the NanoString nCounter PanCancer IO 360 panel. Gene-expression signatures were identified and validated using cross-validated sparse partial least squares modeling and principal component analysis, then correlated with toxicity occurrence.Results A total of 223 and 186 irAEs were observed in the AT and FLT groups, respectively, including arthralgia, colitis, and headache. Distinct gene-expression signatures significantly predicted toxicity occurrence, with variation across therapy settings. Arthralgia was predicted by immune-related and apoptotic gene signatures (eg, SMAD5, FASLG in FLT; ICOS, TGFB2 in AT), while colitis was linked to inflammatory and adhesion-related pathways. In the AT group, headache was associated with genes involved in interferon and adhesion signaling. Across both cohorts, specific signatures predicted overall irAE risk and timing. No events were observed in patients with low-risk signatures over the follow-up period. In the FLT cohort, arthralgia and cutaneous toxicities were positively associated with ORR, while arthralgia, asthenia, colitis, fatigue, and skin-related toxicities correlated with improved disease control rate. No significant association between irAEs and relapse risk was observed in the adjuvant cohort.Conclusions Whole-blood gene-expression profiling enables early identification of patients at high risk for irAEs during anti-PD-1 therapy. These predictive biomarkers may guide personalized toxicity monitoring in melanoma treatment.https://jitc.bmj.com/content/13/7/e011315.full |
| spellingShingle | Michael Bailey Andrew White Francesca Sparano Alessandra Cesano Mariaelena Capone Corrado Caracò Ester Simeone Lucia Festino Alfredo Budillon Sarah Warren Domenico Mallardo Paolo A Ascierto Vito Vanella Ernesta Cavalcanti Claudia Trojaniello Maria Grazia Vitale Margaret Ottaviano Paolo Chiodini Mario Fordellone Bianca Arianna Facchini Maria Ingenito Caterina Costa Rosaria De Filippi Gene-expression signature predicts autoimmune toxicity in metastatic melanoma Journal for ImmunoTherapy of Cancer |
| title | Gene-expression signature predicts autoimmune toxicity in metastatic melanoma |
| title_full | Gene-expression signature predicts autoimmune toxicity in metastatic melanoma |
| title_fullStr | Gene-expression signature predicts autoimmune toxicity in metastatic melanoma |
| title_full_unstemmed | Gene-expression signature predicts autoimmune toxicity in metastatic melanoma |
| title_short | Gene-expression signature predicts autoimmune toxicity in metastatic melanoma |
| title_sort | gene expression signature predicts autoimmune toxicity in metastatic melanoma |
| url | https://jitc.bmj.com/content/13/7/e011315.full |
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