Abstract
Summary
Background
Checkpoint inhibitors bring marked benefits but only in a minority of patients and may also be associated with severe adverse events. Treatment outcome still cannot be faithfully predicted. The following study hypothesized that host genetics could be applied as predictive biomarkers for checkpoint inhibitor response and immune-related adverse events. We conducted a study based on germinal polymorphisms from genes coding for proteins involved in immune regulation.
Methods
Germinal DNA was obtained from advanced cancer patients treated with anti-PD-1/PD-L1 checkpoint inhibitors. DNA was genotyped using a custom panel of 166 single nucleotide polymorphisms covering 86 preselected immunogenetic-related genes. Computational analysis using a GTEX portal was made to determine potential expression Quantitative Trait Loci in tissues.
Results
Ninety-four consecutive patients were included. Objective response rate (complete or partial response) was significantly correlated to tumor microenvironment-related SNPs concerning
CCL2
,
NOS3
,
IL1RN
,
IL12B
,
CXCR3
and
IL6R
genes. Toxicity were linked to target-related gene SNPs including
UNG
,
IFNW1
,
CTLA4
,
PD-L1
and
IFNL4
genes. The Area Under the ROC curve (AUC) was 0.81 (95% CI: 0.72–0.9) for response and 0.89 (95% CI: 0.76–1.00) for toxicity. In silico functionality exploring pointed rs4845618 (
IL6R
), rs10964859 (
IFNW1
) and rs3087243 (
CTLA4
) as potentially impacting gene expression.
Conclusion
These results strongly support a role for distinct immunogenetic-related gene SNPs able to predict efficacy and safety of anti-PD1/PD-L1 therapies. The results highlight the existence of patient-specific, germinal biomarkers able predict response to checkpoint inhibitor efficacy and, possibly, to predict treatment-related adverse events.