CTLA-4 Single-Nucleotide Polymorphism Is Associated with High Response to Anti–PD-1/PD-L1 Immunotherapy in Advanced NSCLC

Targeting PD-1 or its ligand (PD-L1) has been shown to induce an anticancer immune response in a proportion of patients with non–small-cell lung cancer (NSCLC).¹ However, the efficacy of immune checkpoint inhibitors varies among patients. Studies have demonstrated that immune-related adverse events (irAEs) correlate with survival for single-agent anti–PD-1/PD-L1 therapy in NSCLC.² Similarly, combined pharmacologic blockade of a second checkpoint, such as CTLA-4, with PD-1 allows heightened immune activation, resulting in both improved cancer outcomes but more irAEs.²

Studies have demonstrated that inherited heterozygosity for single-nucleotide polymorphisms (SNPs) within and surrounding CTLA-4 is associated with autoimmune diseases, such as autoimmune thyroid disease and rheumatoid arthritis, and type 1 diabetes.^2,3 Based on these findings, Allen and colleagues hypothesized that SNPs impacting CTLA-4 function could be enriched in patients with NSCLC with exceptional response to single-agent anti–PD-1. In this study, exceptional response was defined as progression-free survival of ≥2 years and ≥1 irAEs of Common Terminology Criteria for Adverse Events grade ≥2.²

The researchers performed whole-genome sequencing on germline DNA from 35 prospectively recruited patients meeting these criteria from a treatment pool of >700 patients. The frequency of a curated list of SNPs located within a 200-kilobase region encompassing CTLA-4 was analyzed and compared with patients with lung cancer within the Pan-Cancer Analysis of Whole Genomes (PCAWG) and with cancer- and dementia-free elderly individuals in the Medical Genome Reference Bank (MGRB).²

Several noncoding SNPs enriched within the exceptional responders compared with control populations were identified using linear regression analysis. It is interesting to note that one of these SNPs was found in 15.7% of exceptional responders, which was twice the frequency of comparable cases within PCAWG and almost 4 times more than MGRB and remained statistically significant following rigorous adjustment. This noncoding SNP is reported to exhibit differential enhancer activity and has been associated with rheumatoid arthritis and type 1 diabetes. Its enrichment within the exceptional responders suggests that the altered CTLA-4 function may cooperate with the blockade of PD-1 to confer a higher immune response.²

The investigators concluded that this common variant might serve as a response biomarker for single-agent anti–PD-1 treatment or may comprise a potential therapeutic target. Preclinical analyses and validation within an independent cohort are underway.

References

1. Li H, van der Merwe PA, Sivakumar S. Biomarkers of response to PD-1 pathway blockade. Br J Cancer. 2022;126:1663-1675.
2. Allen IA, Russell A, Jackson KL, et al. Correlation between a CTLA-4 single nucleotide polymorphism and high response to anti-PD1/PDL1 immunotherapy in advanced non small cell lung cancer. Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract 665.
3. Wolff AS, Mitchell AL, Cordell HJ, et al. CTLA-4 as a genetic determinant in autoimmune Addison’s disease. Genes Immun. 2015;16:430-436.