TY - JOUR
T1 - Pretreatment tissue TCR repertoire evenness is associated with complete pathologic response in patients with NSCLC receiving neoadjuvant chemoimmunotherapy
AU - Casarrubios, Marta
AU - Cruz-Bermúdez, Alberto
AU - Nadal, Ernest
AU - Insa, Amelia
AU - del Rosario García Campelo, María
AU - Lázaro, Martín
AU - Dómine, Manuel
AU - Majem, Margarita
AU - Rodríguez-Abreu, Delvys
AU - Martínez-Martí, Alex
AU - de Castro-Carpeño, Javier
AU - Cobo, Manuel
AU - López-Vivanco, Guillermo
AU - Del Barco, Edel
AU - Caro, Reyes Bernabé
AU - Viñolas, Nuria
AU - Aranda, Isidoro Barneto
AU - Viteri, Santiago
AU - Massuti, Bartomeu
AU - Barquín, Miguel
AU - Laza-Briviesca, Raquel
AU - Sierra-Rodero, Belén
AU - Parra, Edwin R.
AU - Sanchez-Espiridion, Beatriz
AU - Rocha, Pedro
AU - Kadara, Humam
AU - Wistuba, Ignacio I.
AU - Romero, Atocha
AU - Calvo, Virginia
AU - Provencio, Mariano
N1 - Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/11/15
Y1 - 2021/11/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-1200
DO - 10.1158/1078-0432.CCR-21-1200
M3 - Article
C2 - 34376534
AN - SCOPUS:85113946731
SN - 1078-0432
VL - 27
SP - 5878
EP - 5890
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -