Pretreatment Tissue TCR Repertoire Evenness Is Associated with Complete Pathologic Response in Patients with NSCLC Receiving Neoadjuvant Chemoimmunotherapy.
Por:
Casarrubios M, Cruz-Bermudez A, Nadal E, Insa A, Garcia-Campelo R, Lazaro M, Domine M, Majem M, Rodriguez-Abreu D, Martinez-Marti A, de Castro-Carpeno J, Cobo M, Lopez-Vivanco G, Del Barco E, Bernabe Caro R, Vinolas N, Barneto Aranda I, Viteri S, Massuti B, Barquin M, Laza-Briviesca R, Sierra-Rodero B, Parra E, Sanchez-Espiridion B, Rocha P, Kadara H, Wistuba I, Romero A, Calvo V, Provencio M
Publicada:
1 nov 2021
Ahead of Print:
10 ago 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 = 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.
Filiaciones:
Casarrubios M:
Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de Hierro, Hospital Universitario Puerta de Hierro-Majadahonda
Cruz-Bermudez A:
Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de Hierro, Hospital Universitario Puerta de Hierro-Majadahonda
Nadal E:
Department of Medical Oncology, Catalan Institute of Oncology
Insa A:
Medical Oncology, Fundación INCLIVA, Hospital Clínico Universitario de Valencia, Valencia, Spain
Garcia-Campelo R:
Medical Oncology, Complejo Hospitalario Universitario La Coruña
Lazaro M:
Medical Oncology, Hospital Universitario de Vigo, Pontevedra, Spain
Domine M:
Oncology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz
Majem M:
Oncology, Hospital de Sant Pau
Rodriguez-Abreu D:
Hospital Universitario Insular de Gran Canaria
Martinez-Marti A:
Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain
de Castro-Carpeno J:
Oncology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz
Cobo M:
Medical Oncology, Medical Oncology Intercenter Unit. Regional and Virgen de la Victoria University Hospitals. IBIMA. Málaga. Spain
Lopez-Vivanco G:
Medical Oncology, Cruces Hospital
Del Barco E:
Oncología, Hospital Universitario de Salamanca, Salamanca, Spain
Bernabe Caro R:
medical Oncology, Hospital Universitario Virgen del Rocio, Sevilla, Spain
Vinolas N:
Medical Oncology, Hospital Clinic
Barneto Aranda I:
Hospital Universitario Reina Sofia, Córdoba, Spain
Viteri S:
Medical Oncology Service, Dr Rosell Oncology Institute. Dexeus University Hospital
Massuti B:
Department of Medical Oncology, Hospital General Universitario de Alicante
Barquin M:
Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de Hierro, Hospital Universitario Puerta de Hierro-Majadahonda
Laza-Briviesca R:
Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de Hierro, Hospital Universitario Puerta de Hierro-Majadahonda
Parra E:
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center
Medical Oncology, Hospital La Paz, Madrid,Translational Oncology Unit
hybrid, Green Published
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