Genetic Polymorphisms in Immune Checkpoint Regulation

Genetic polymorphisms within genes encoding immune checkpoints—particularly programmed cell death protein 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)—have emerged as critical determinants of immunological tolerance, cancer susceptibility and therapeutic response. Single-nucleotide polymorphisms (SNPs) or rare structural variants in promoter, enhancer or untranslated regions can modulate receptor and ligand expression, influence transcription factor binding, and alter microRNA interaction, thereby shifting the balance between T cell activation and inhibition. Such variation underpins inter-individual differences in autoimmunity, tumour immune escape and the efficacy of immune-checkpoint inhibitors. Insights into allele-specific effects have informed biomarker development for patient stratification and have sparked interest in liquid biopsy approaches to capture circulating tumour DNA. Taken together, this body of work highlights the global significance of immune-checkpoint polymorphisms in guiding precision immunotherapy, anticipating adverse events and unravelling the genetic architecture of immune regulation.

Research from Nature Portfolio

Two seminal studies have correlated PD-L1 gene variants with clinical outcomes in advanced non-small-cell lung cancer. In one investigation, the rs2282055 and rs4143815 SNPs were assessed in patients receiving nivolumab; carriers of the favourable alleles exhibited significantly higher objective response rates and longer progression-free survival compared to alternative genotypes. A parallel study evaluated the impact of rs2297136 and rs4143815 in individuals undergoing first-line paclitaxel-cisplatin chemotherapy; patients bearing the combined variant haplotype showed improved chemotherapeutic response and overall survival. Both works underscored the utility of PD-L1 polymorphisms as predictive biomarkers and provided a foundation for integrating genotype data into therapeutic decision-making.

Genetic Polymorphisms in Immune Checkpoint Regulation publication trend

The graph below shows the total number of articles in genetic polymorphisms in immune checkpoint regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Genetic polymorphism: A heritable DNA sequence variation present in at least 1% of the population, which may affect gene function or regulation.

Immune checkpoint: A regulatory pathway in the immune system that maintains self-tolerance and modulates the duration and amplitude of immune responses.

Single-nucleotide polymorphism (SNP): The substitution of a single nucleotide at a specific position in the genome, which can influence gene expression or protein activity.

Promoter/enhancer region: Non-coding DNA sequences that bind transcription factors to initiate or increase gene transcription.

Untranslated region (UTR): The 5′ or 3′ segments of mRNA that are not translated into protein but can regulate transcript stability and translation efficiency.

Allele: One of two or more alternative forms of a gene or genetic locus found at the same place on a chromosome.

References

1. rs822336 binding to C/EBPβ and NFIC modulates induction of PD-L1 expression and predicts anti-PD-1/PD-L1 therapy in advanced NSCLC. Molecular Cancer (2024).
2. Non-invasive plasma testing for CD274 UTR structural variations by next-generation sequencing in cancer. Cell Death Discovery (2023).
3. The susceptibility of single nucleotide polymorphisms located within co-stimulatory pathways to systemic lupus erythematosus. Frontiers in Immunology (2024).
4. Clinical Impact of Single Nucleotide Polymorphism in PD-L1 on Response to Nivolumab for Advanced Non-Small-Cell Lung Cancer Patients. Scientific Reports (2017).
5. PD-L1 polymorphism can predict clinical outcomes of non-small cell lung cancer patients treated with first-line paclitaxel-cisplatin chemotherapy. Scientific Reports (2016).