ANN ARBOR, MI – Lung cancer outcomes have been significantly improved with the use of immune checkpoint inhibitors (ICI), although some patients derive only limited benefit from the therapy and others experience potentially serious toxicities.
That’s why a new study involving the University of Michigan, the VA Ann Arbor, MI, Healthcare System and colleagues sought to identify biomarkers that would predict survival when ICI is used to treat metastatic non-small cell lung cancer (mNSCLC).
“Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker,” the researchers wrote in Scientific Reports.1
To learn more, the study team performed HLA typing on 85 patients with mNSCLC, on ICI therapy, and analyzed the effect of HLA Class II genotype on progression-free survival (PFS), overall survival (OS), and irAEs. Most of the patients, 83.5%, received pembrolizumab.
“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]),” the authors pointed out. “PFS did not reach significance (univariate, p = 0.12, 8.2 months vs 5.1 months). Eleven patients developed endocrine irAEs.”
The study determined that HLA-DRB4 was the predominant genotype among these patients (9/11, 81.8%), adding, “Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139).”
The researchers advised that their study was 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,” they wrote.
Background information in the article pointed out that there are many reasons for lack of benefit to ICIs. “Preclinical and translational studies have identified primary and acquired mechanisms of resistance including hepatic siphoning, tumoral loss of HLA Class I, T cell chemokine silencing, and immunometabolic checkpoints,” it explained. “In parallel, preclinical and translational studies have begun to identify potential cellular mediators of irAEs, including hepatitis, thyroiditis, and colitis. Given the importance of antigen presentation to immune responses, studies are beginning to link HLA genotypes to ICI efficacy and toxicity. However, many of these studies have focused on HLA class I genotypes rather than HLA class II genotypes.”
According to the study team, this research “revealed a significant correlation between HLA-DRB4 and improved OS, on both univariable and multivariable analysis. To our knowledge, this is the first such report.”
The key finding was that patients carrying HLA-DRB4 had the longest median OS of 26.3 months. The researchers also explored the impact of DRB4 allelic variation on survival but did not find any significant differences between the allelic variations, although they added that the study wasn’t powered to make definitive conclusions for allelic variations.
The article also discussed how other studies have reported associations between MHC class II and ICI efficacy. Among those findings were longer survival in patients who were heterozygous for HLA DRB1 and that increased expression of MHC class II was associated with improved survival. More recently, the researchers noted, HLA-A*03 has been associated with inferior outcomes in patients receiving ICIs.
“In our study, we did note a trend towards HLA-A*03 having worse survival outcomes, but it was not statistically significant. The lack of significance may be due to the small sample size of this study leading to inadequate power to detect a difference,” they posited. “Other groups have described an inverse correlation between loss of heterozygosity (LOH) for HLA Class I and II loci in tumors with survival.”
Past research also has suggested that on-treatment samples provide more information about clinical benefit when using HLA class II gene expression as an indicator of response. “It is proposed that the activation of CD4+ T cells by HLA class II expression helps to initiate CD8+ T cells that consequently mount a successful antitumor immune response during ICI therapy. Collectively, these data highlight the contribution of MHC class II mediated immune responses to therapeutic anti-tumor immune responses,” the study stated.
The researchers also advised that they found a significant association between HLA-DRB4 and incidence of endocrine irAEs. “We found an overrepresentation of HLA-DRB4 in 13 of the 20 patients with any degree of irAEs and nine of the 11 patients with endocrine irAEs. In comparison, only 40–50% of the general Caucasian population carry HLA-DRB4. This observation has not been previously reported,” they explained.
They concluded that, while their study had important findings, it was small. The authors called for future larger studies to validate the findings of HLA-DRB4 as a predictive marker for survival and development of endocrine irAEs. “Additionally, mechanistic studies aimed at understanding if there are conserved antigens presented by HLA-DRB4 that contribute to both irAE and anti-tumor immunity are needed,” the study noted.
- Jiang CY, Zhao L, Green MD, Ravishankar S, et. Al. Class II HLA-DRB4 is a predictive biomarker for survival following immunotherapy in metastatic non-small cell lung cancer. Sci Rep. 2024 Jan 3;14(1):345. doi: 10.1038/s41598-023-48546-y. PMID: 38172168; PMCID: PMC10764770.