Contrasting outcomes of inherited <i>NOD2</i> loss-of-function variants on immunotherapy response in cancer

We have read with great interest the recent article by Barnet et al. ( 1 ), which reported in Non-Small Cell Lung Cancer (NSCLC) patients a significantly higher frequency (30%) of NOD2 loss-of-function (LOF) variants in exceptional anti-PD-1/PD-L1 responders with immune-related adverse events (irAEs) > 2. This work expands our understanding of how inherited germline variants may help predict immunotherapy response and adverse events in lung cancer.However, we wish to share some observations from a study conducted in our laboratory on a Mediterranean cohort, which revealed a distinct spectrum and opposite outcomes, despite using a similar approach to that of Barnet's study.We analyzed 117 metastatic NSCLC patients treated with anti-PD-1/PD-L1 at two Spanish centers (2019-2024), assessing toxicity following Common Terminology Criteria for Adverse Events (CTCAE v5) and response at 3, 6, and 12 mo, as well as germline variation by whole exome sequencing plus imputation.Focusing on NOD2 gene ( Fig. 1 ), we identified NOD2 variants in 32 patients (27.35%), a frequency nearly identical to that reported by Barnet.However, NOD2 variant carriers in our cohort generally showed poor treatment responses: Only 34.48% of NOD2 -variant carriers in our cohort-maintained response at 12 mo, compared with the 70 to 80% exceptional response rates reported by Barnet.Moreover, using their 24-mo Progression-Free Survival (PFS) criterion, we project that only 15 to 20% of our NOD2 -variant carriers would qualify as exceptional responders, a fourfold to fivefold lower rate than their findings.