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, Campelo, MDG, Lazaro, M, Domine, M, Majem, M, Rodriguez-Abreu, D, Martinez-Marti, A, de Castro-Carpeno, J, Cobo, M, Lopez-Vivanco, G, Del Barco, E, Caro, RB, Vinolas, N, Aranda, IB, Viteri, S, Massuti, B, Barquin, M, Laza-Briviesca, R, Sierra-Rodero, B, Parra, ER, Sanchez-Espiridion, B, Rocha, P, Kadara, H, Wistuba, II, Romero, A, Calvo, V, Provencio, M
Publicada:
1 nov 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 nonsmall 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 nonCPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined.
Results: Wehave 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:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia Ar, Serv Oncol Med, Madrid, Spain
Cruz-Bermudez, A:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia Ar, Serv Oncol Med, Madrid, Spain
Nadal, E:
Inst Catala Oncol, Barcelona, Spain
Insa, A:
Hosp Clin Univ Valencia, Fdn INCLIVA, Valencia, Spain
Campelo, MDG:
Hosp Univ A Coruna, La Coruna, Spain
Lazaro, M:
Hosp Univ Vigo, Pontevedra, Spain
Domine, M:
Hosp Univ Fdn Jimenez Diaz, Madrid, Spain
Majem, M:
Hosp Santa Creu & Sant Pau, Barcelona, Spain
Rodriguez-Abreu, D:
Hosp Insular Gran Canaria, Las Palmas Gran Canaria, Spain
Martinez-Marti, A:
Hosp Univ & Inst Oncol Vall dHebron VHIO, Barcelona, Spain
de Castro-Carpeno, J:
Hosp Univ La Paz, Madrid, Spain
Cobo, M:
Hosp Univ Reg Malaga, Malaga, Spain
Lopez-Vivanco, G:
Hosp Univ Cruces, Baracaldo, Spain
Del Barco, E:
Hosp Univ Salamanca, Salamanca, Spain
Caro, RB:
Hosp Univ Virgen del Rocio, Seville, Spain
Vinolas, N:
Hosp Clin Barcelona, Barcelona, Spain
Aranda, IB:
Hosp Univ Reina Sofia, Cordoba, Spain
Viteri, S:
Hosp Univ Quiron Dexeus, Inst Oncol Dr Rosell, Grp QuironSalud, Barcelona, Spain
Massuti, B:
Hosp Gen Alicante, Alicante, Spain
Barquin, M:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia Ar, Serv Oncol Med, Madrid, Spain
Laza-Briviesca, R:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia Ar, Serv Oncol Med, Madrid, Spain
Sierra-Rodero, B:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia Ar, Serv Oncol Med, Madrid, Spain
Parra, ER:
Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
Sanchez-Espiridion, B:
Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
Rocha, P:
Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
Kadara, H:
Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
Wistuba, II:
Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
Romero, A:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia Ar, Serv Oncol Med, Madrid, Spain
Calvo, V:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia Ar, Serv Oncol Med, Madrid, Spain
Provencio, M:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia Ar, Serv Oncol Med, Madrid, Spain
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