Understanding immune escape in lung cancer

Treatment resistance can be a turning point in the journey of a patient with cancer, but the genetic path to it remains unclear. Bakir et al. studied this in the context of neopeptide vaccines (NPVs) — a therapy whereby the patient is immunized with tumor-specific peptides. An NPV was designed for a patient with EGFR-mutant lung cancer whose disease had progressed despite multiple lines of treatment. The vaccine included peptides from ten tumor-derived mutations — one of which was an EGFR exon 19 deletion (ex19del) that sequencing data suggested occurred after a clonal whole-genome doubling (WGD) event. Signs of T cell reactivity toward ex19del were found, but the data suggested that this response was muted. The patient unfortunately went on to develop a liver metastasis, which could be traced to an EGFR wild-type clone that had existed pre-vaccination. This metastasis had an immunosuppressive tumor microenvironment and retained expression of vaccine-targeted neoantigens acquired pre-WGD but not after it, suggesting that the former might be more potent NPV targets. The team also hypothesize that combining NPVs with immunotherapies might boost their efficacy. More studies will be needed to confirm this, but for now, this elegant work shows how understanding the mechanisms of immune escape may help to prevent it.

Original reference: Nature https://doi.org/10.1038/s41586-025-08586-y (2025)