TY - JOUR
T1 - Distinctive germline expression of class i human leukocyte antigen (HLA) alleles and DRB1 heterozygosis predict the outcome of patients with non-small cell lung cancer receiving PD-1/PD-L1 immune checkpoint blockade
AU - Correale, Pierpaolo
AU - Saladino, Rita Emilena
AU - Giannarelli, DIana
AU - Giannicola, Rocco
AU - Agostino, Rita
AU - Staropoli, Nicoletta
AU - Strangio, Alessandra
AU - Del Giudice, Teresa
AU - Nardone, Valerio
AU - Altomonte, Maria
AU - Pastina, Pierpaolo
AU - Tini, Paolo
AU - Falzea, Antonia Consuelo
AU - Imbesi, Natale
AU - Arcati, Valentina
AU - Romeo, Giuseppa
AU - Caracciolo, Daniele
AU - Luce, Amalia
AU - Caraglia, Michele
AU - Giordano, Antonio
AU - Pirtoli, Luigi
AU - Necas, Alois
AU - Amler, Evzen
AU - Barbieri, Vito
AU - Tassone, Pierfrancesco
AU - Tagliaferri, Pierosandro
N1 - Funding Information:
This work has been supported by the NSP project nos. LO1508 and LO1309, MZ-VES project nos. 16-28637A, 16-2960A, and 17-32285A, and by funds institutional research (TA 29) of UVPS Brno.
Publisher Copyright:
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/17
Y1 - 2020/6/17
N2 - Background Nivolumab is a human monoclonal antibody against programmed cell death receptor-1 (PD-1) able to rescue quiescent tumor infiltrating cytotoxic T lymphocytes (CTLs) restoring their ability to kill target cells expressing specific tumor antigen-derived epitope peptides bound to homologue human leukocyte antigen (HLA) molecules. Nivolumab is currently an active but expensive therapeutic agent for metastatic non-small cell lung cancer (mNSCLC), producing, in some cases, immune-related adverse events (irAEs). At the present, no reliable biomarkers have been validated to predict either treatment response or adverse events in treated patients. Methods We performed a retrospective multi-institutional analysis including 119 patients with mNSCLC who received PD-1 blockade since November 2015 to investigate the predictive role of germinal class I HLA and DRB1 genotype. We investigated the correlation among patients' outcome and irAEs frequency with specific HLA A, B, C and DRB1 alleles by reverse sequence-specific oligonucleotide (SSO) DNA typing. Results A poor outcome in patients negative for the expression of two most frequent HLA-A alleles was detected (HLA: HLA-A∗01 and or A∗02; progression-free survival (PFS): 7.5 (2.8 to 12.2) vs 15.9 (0 to 39.2) months, p=0.01). In particular, HLA-A∗01-positive patients showed a prolonged PFS of 22.6 (10.2 to 35.0) and overall survival (OS) of 30.8 (7.7 to 53.9) months, respectively. We also reported that HLA-A and DRB1 locus heterozygosis (het) were correlated to a worse OS if we considered het in the locus A; in reverse, long survival was correlated to het in DRB1. Conclusions This study demonstrate that class I and II HLA allele characterization to define tumor immunogenicity has relevant implications in predicting nivolumab efficacy in mNSCLC and provide the rationale for further prospective trials of cancer immunotherapy.
AB - Background Nivolumab is a human monoclonal antibody against programmed cell death receptor-1 (PD-1) able to rescue quiescent tumor infiltrating cytotoxic T lymphocytes (CTLs) restoring their ability to kill target cells expressing specific tumor antigen-derived epitope peptides bound to homologue human leukocyte antigen (HLA) molecules. Nivolumab is currently an active but expensive therapeutic agent for metastatic non-small cell lung cancer (mNSCLC), producing, in some cases, immune-related adverse events (irAEs). At the present, no reliable biomarkers have been validated to predict either treatment response or adverse events in treated patients. Methods We performed a retrospective multi-institutional analysis including 119 patients with mNSCLC who received PD-1 blockade since November 2015 to investigate the predictive role of germinal class I HLA and DRB1 genotype. We investigated the correlation among patients' outcome and irAEs frequency with specific HLA A, B, C and DRB1 alleles by reverse sequence-specific oligonucleotide (SSO) DNA typing. Results A poor outcome in patients negative for the expression of two most frequent HLA-A alleles was detected (HLA: HLA-A∗01 and or A∗02; progression-free survival (PFS): 7.5 (2.8 to 12.2) vs 15.9 (0 to 39.2) months, p=0.01). In particular, HLA-A∗01-positive patients showed a prolonged PFS of 22.6 (10.2 to 35.0) and overall survival (OS) of 30.8 (7.7 to 53.9) months, respectively. We also reported that HLA-A and DRB1 locus heterozygosis (het) were correlated to a worse OS if we considered het in the locus A; in reverse, long survival was correlated to het in DRB1. Conclusions This study demonstrate that class I and II HLA allele characterization to define tumor immunogenicity has relevant implications in predicting nivolumab efficacy in mNSCLC and provide the rationale for further prospective trials of cancer immunotherapy.
KW - antigen presentation
KW - B7-H1 antigen
KW - lung neoplasms
KW - tumor biomarkers
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U2 - 10.1136/jitc-2020-000733
DO - 10.1136/jitc-2020-000733
M3 - Article
C2 - 32554614
AN - SCOPUS:85086691605
VL - 8
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
SN - 2051-1426
IS - 1
M1 - e000733
ER -