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Updated: Jul 6, 2025
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Class II HLA-DRB4 is a predictive biomarker for survival following immunotherapy in metastatic non-small cell lung
Cindy Y Jiang1,2, Lili Zhao3, Michael D Green4
1Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Abstract:
Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated with improved OS in both univariate (p = 0.022; 26.3 months vs 10.2 months) and multivariate analysis (p = 0.011, HR 0.49, 95% CI [0.29, 0.85]). PFS did not reach significance (univariate, p = 0.12, 8.2 months vs 5.1 months). Eleven patients developed endocrine irAEs. HLA-DRB4 was the predominant genotype among these patients (9/11, 81.8%). Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139). Our study is the first to suggest that patients with metastatic NSCLC patients on ICI therapy with HLA-DRB4 genotype experience improved survival outcomes. Patients with HLA-DRB4 had the longest median OS (26.3 months). Additionally, we found a correlation between HLA-DRB4 and the occurrence of endocrine irAEs.
Insights
Human Leukocyte Antigen (HLA) Class II genotype, specifically HLA-DRB4, may predict outcomes for metastatic non-small cell lung cancer (mNSCLC) patients receiving immune checkpoint inhibitors (ICI). HLA-DRB4 presence correlated with improved overall survival but also increased endocrine immune-related adverse events.
Area of Science:
- Immunogenomics
- Oncology
- Translational Medicine
Background:
- Immune checkpoint inhibitors (ICIs) are crucial for metastatic non-small cell lung cancer (mNSCLC), yet patient response and toxicity vary.
- Germline genetic factors influencing ICI efficacy and adverse events are poorly understood.
- Human Leukocyte Antigen (HLA) genes are emerging as potential predictive biomarkers for ICI therapy.
Purpose of the Study:
- To investigate the impact of HLA Class II genotype on progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) in mNSCLC patients treated with ICIs.
- To identify specific HLA genotypes associated with differential responses to ICI therapy.
Main Methods:
- HLA typing was performed on 85 mNSCLC patients undergoing ICI treatment.
- Statistical analyses, including univariate and multivariate models, were used to assess the correlation between HLA genotype (specifically HLA-DRB4) and clinical outcomes (PFS, OS, irAEs).
- Pembrolizumab was the primary ICI used in the majority of patients.
Main Results:
- The HLA-DRB4 genotype was present in 40% of patients and was significantly associated with improved OS (median 26.3 months vs. 10.2 months, p=0.022).
- No significant correlation was found between HLA-DRB4 and PFS.
- Patients with HLA-DRB4 had a higher incidence of endocrine irAEs (81.8% of endocrine irAE cases, p=0.0139).
Conclusions:
- This study suggests HLA-DRB4 as a potential predictive biomarker for improved overall survival in mNSCLC patients treated with ICIs.
- The presence of HLA-DRB4 is also linked to an increased risk of endocrine immune-related adverse events.
- Further research is warranted to elucidate the mechanisms underlying HLA-DRB4's role in ICI response and toxicity.
