Pretreatment tissue TCR repertoire evenness is associated with complete pathologic response in patients with NSCLC receiving neoadjuvant chemoimmunotherapy
Casarrubios, Marta (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Cruz-Bermúdez, Alberto (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Nadal, Ernest (Institut Català d'Oncologia)
Insa, Amelia (Hospital Clínic Universitari (València))
García Campelo, María del Rosario (Complejo Hospitalario Universitario de A Coruña)
Lázaro, Martín (Hospital Universitario de Vigo)
Dómine Gómez, Manuel (Hospital Universitario Fundación Jiménez Díaz)
Majem, Margarita (Institut d'Investigació Biomèdica Sant Pau)
Rodríguez-Abreu, Delvys (Hospital Universitario Insular de Gran Canaria)
Martinez-Marti, Alex (Vall d'Hebron Institut d'Oncologia)
de Castro, Javier (Hospital Universitario La Paz (Madrid))
Cobo, Manuel (Hospital Regional Universitario de Málaga)
López-Vivanco, Guillermo (Hospital Universitario de Cruces (Barakaldo, País Basc))
Del Barco Morillo, Edel (Hospital Universitario de Salamanca)
Bernabé, Reyes (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Viñolas, Nuria (Hospital Clínic i Provincial de Barcelona)
Barneto Aranda, Isidoro (Hospital Universitario Reina Sofía (Còrdova, Espanya))
Viteri, Santiago (Instituto Oncológico Dr. Rosell. Hospital Universitario Quiron Dexeus)
Massuti, Bartomeu (Hospital General Universitario de Alicante (Alacant, País Valencià))
Barquín, Miguel (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Laza-Briviesca, Raquel (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Sierra-Rodero, Belén (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Parra, Edwin R. (The University of Texas. Department of Translational Molecular Pathology)
Sanchez-Espiridion, Beatriz (The University of Texas. Department of Translational Molecular Pathology)
Rocha, Pedro (The University of Texas. Department of Translational Molecular Pathology)
Kadara, Humam (The University of Texas. Department of Translational Molecular Pathology)
Wistuba, Ignacio I. (The University of Texas. Department of Translational Molecular Pathology)
Romero, Atocha (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Calvo, Virginia (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Provencio, Mariano (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))

Fecha:	2021
Resumen:	Purpose: Characterization of the T-cell receptor (TCR) repertoire may be a promising source for predictive biomarkers of pathologic response to immunotherapy in locally advanced non-small cell lung cancer (NSCLC). Experimental Design: In this study, next-generation TCR sequencing was performed in peripheral blood and tissue samples of 40 patients with NSCLC, before and after neoadjuvant chemoimmunotherapy (NADIM clinical trial, NCT03081689), considering their complete pathologic response (CPR) or non-CPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined. Results: We have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequently ranked clones (top 1%) present in diagnostic biopsies occupied greater frequency in the total clonal space of CPR patients, achieving an AUC ROC to identify CPR patients of 0. 967 (95% confidence interval, 0. 897-1. 000; P ¼ 0. 001), and improving the results of PD-L1 tumor proportion score (TPS; AUC = 0. 767; P = 0. 026) or tumor mutational burden (TMB; AUC = 0. 550; P = 0. 687). Furthermore, tumors with high pretreatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selective expansion of pretreatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveillance, which could explain the high survival rate of these patients. Conclusions: We have identified two parameters derived from TCR repertoire analysis that could outperform PD-L1 TPS and TMB as predictive biomarkers of CPR after neoadjuvant chemoimmunotherapy, and unraveled possible mechanisms of CPR involving enhanced tumor immunogenicity and peripheral immunosurveillance.
Ayudas:	Instituto de Salud Carlos III PI19/01652 Instituto de Salud Carlos III CD19/00170 Instituto de Salud Carlos III IFI18/00051 Ministerio de Ciencia e Innovación RTC2017-6502-1 Ministerio de Ciencia e Innovación RTC2019-007359-1 BLI-O European Commission. Horizon 2020 875160 European Commission PEJ16/MED/AI-1972 European Commission PEJD-2018-PRE/SAL-8641
Nota:	Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER); Comunidad de Madrid. Consejería de Ciencia, Universidades e Innovación (PEJD-2019-PRE/BMD-17006).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Aged ; Carcinoma, Non-Small-Cell Lung ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Immunotherapy ; Lung Neoplasms ; Male ; Middle Aged ; Neoadjuvant Therapy ; Prospective Studies ; Receptors, Antigen, T-Cell ; Treatment Outcome
Publicado en:	Clinical Cancer Research, Vol. 27 Núm. 21 (November 2021) , p. 5878-5890, ISSN 1557-3265

DOI: 10.1158/1078-0432.CCR-21-1200
PMID: 34376534

13 p, 941.6 KB

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