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

Abstract

BackgroundNivolumab 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.MethodsWe 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.ResultsA 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.ConclusionsThis 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.

Neutrophil to lymphocyte ratio influences impact of steroids on efficacy of immune checkpoint inhibitors in lung cancer brain metastases

“…Since the start of ICI clinical trials, determining which patients will respond best to ICI has been a goal of clinicians and scientists. For example, reseachers have found that patients negative for the expression of the two most frequent HLA-A alleles a worse prognosis in NSCLC treated with ICI 28 , 29 . Others have found that commonly utilized medications like systemic antibiotics and proton-pump inhibitors can decrease the efficacy of ICIs 30 .…”

HLA Expression Correlates to the Risk of Immune Checkpoint Inhibitor-Induced Pneumonitis

“…As shown in previous reports, class I and II HLA allele profiling have been correlated to either treatment response or survival in cancer patients receiving immune checkpoint blockade [ 27 , 28 , 29 ]. In fact, HLA complex plays a critical role in both the efficiency and modulation of the T cell-mediated immune response, performing the specific function of presenting tumor antigen-derived peptides to specific T cell receptors on effector T cells [ 26 , 27 , 28 ]. The epitope number as well as the peptide affinity for HLA molecules is haplotype specific, thus the same antigen may have different immunogenicity in individuals with different HLA profiles.…”

Immune Checkpoint Expression on Immune Cells of HNSCC Patients and Modulation by Chemo- and Immunotherapy

“…Another factor that directly influences the effect of immunotherapy are the human leukocyte antigen (HLA) alleles in tumor patients. A recent study demonstrated a predictive role of germinal class I HLA and DRB1 genotype for treatment with the PD-1 inhibitor nivolumab [ 34 ]. The results indicated a poor outcome in patients with non-small cell lung cancer who were negative for the most frequent HLA-A alleles, whereas patients expressing HLA-A*01 displayed prolonged progression-free survival and overall survival [ 34 ].…”

“…A recent study demonstrated a predictive role of germinal class I HLA and DRB1 genotype for treatment with the PD-1 inhibitor nivolumab [ 34 ]. The results indicated a poor outcome in patients with non-small cell lung cancer who were negative for the most frequent HLA-A alleles, whereas patients expressing HLA-A*01 displayed prolonged progression-free survival and overall survival [ 34 ]. A link between specific HLA haplotypes and the expression of immune checkpoints in HNSCC patients is conceivable [ 35 ] and should be investigated in future studies to find reliable biomarkers for effective immunotherapy and to protect patients that do not benefit from these therapies because of severe immune-related adverse events.…”