PD-L1 Expression, Tumor Mutational Burden, and Cancer Gene Mutations Are Stronger Predictors of Benefit from Immune Checkpoint Blockade than HLA Class I Genotype in Non–Small Cell Lung Cancer

Abstract

Introduction: Immune checkpoint blockade (ICB) has revolutionized the treatment of NSCLC, but only approximately 15% of patients achieve durable benefit. Understanding mechanisms of resistance to ICB is pivotal in developing more effective treatment strategies. Recent studies showed that human leukocyte antigen (HLA) class I heterozygosity might be important in mediating benefit from ICB. We aimed to investigate the impact of HLA class I genotype on outcomes of patients with NSCLC treated with ICB. Methods: We collected HLA typing, genomic, and clinical data from patients with advanced NSCLC treated with ICB at M. D. Anderson Cancer Center. We compared HLA class Iheterozygous and HLA class I-homozygous patients for progression-free survival (PFS) and overall survival (OS). HLA I supertype/alleles were also analyzed. To validate our findings, we also analyzed two previously published independent cohorts of patients with NSCLC (the CheckMate-012 and Chowell cohorts). Results: No significant correlations were observed for HLA class I zygosity and PFS or OS in the M. D. Anderson Cancer Center (n ¼ 200), CheckMate-012 (n ¼ 75), or Chowell (n ¼ 371) cohorts. No HLA class I supertype/allele was consistently shown to be correlated with PFS or OS. Predictors of worse outcome across the three cohorts included presence of targetable driver mutation, serine/threonine kinase 11

Prognostic value of HLA-I homozygosity in patients with non-small cell lung cancer treated with single agent immunotherapy

“…Our results are in contrast with the report by Negrao et al, 24 which did not find a significant correlation between HLA zygosity and survival in an NSCLC cohort treated with PD-1/PDL1 at the M. D. Anderson Cancer Center. Notably, a large proportion (25%) of their patient cohort received anti-PD-1/PDL1 as third-line therapy, while all our study participants were treated either in the first-line or second-line setting.…”

“…[16][17][18][19][20][21][22] However, the effect of low HLA genetic diversity (or homozygosity) on response to immunotherapy has not been explored, with the exception of two recent studies. 23 24 Chowell et al investigated the relationship between genetic HLA homozygosity and survival in 100 NSCLC and 269 patients with melanoma treated with immunotherapy, either with anti-PD1/PDL1 or anti-CTLA4 or both. Reduced survival was correlated with homozygosity in at least one HLA-I locus.…”

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

“…Moreover, the authors suggest that decreased expression of MHC class I and antigen presentation through MHC class II should be evaluated in NSCLC to predict response to ICB. 22 In this context, our analysis confirmed the previous finding that occurrence of irAEs, AAbs rise, a low baseline inflammatory status and the kind of chemotherapy regimen received prior PD-1 blockade were all correlated to patients' survival. 23 Class II HLA molecules alike HLA-DRB1 bind peptides recognized by T cell receptors (TCRs) on CD4 + T cells with helper and/or T regulatory function; thus, they can modulate the differentiation and the proliferation of other lymphocyte subsets including CTLs and B cells.…”

The Promises and Challenges of Tumor Mutation Burden as an Immunotherapy Biomarker: A Perspective from the International Association for the Study of Lung Cancer Pathology Committee

“…91 In a recent study on 646 NSCLC from three independent cohorts, the HLA-I genotype did not correlate with the outcome after ICI treatment. 92 An alternative explanation is that other mechanisms are more relevant in lung cancer (e.g., decreased expression of HLA class I). 91 A T-cell exposed to a specific antigen is activated and clonally expands.…”