Clonal Heterogeneity in Non-Small Cell Lung Cancer and the Possible Role in Predicting Response to Treatment with Immune Checkpoint Inhibitors

Immune oncology treatment with immune checkpoint inhibitors (ICIs) is revolutionizing therapeutic approach for advanced non-small cell lung cancer (NSCLC) patients, in terms of longer survival and improved quality of life. To date, the widely used and approved biomarker is programmed death ligand 1 (PD-L1) expression on tumour cells, but it is considered not accurate and it is more likely that many factors, related to both cancer and host, may better predict response to ICI. Among those factors, great attention is being dedicated to tumour mutation burden, defined as the number of somatic non-synonymous mutations in cancer cells assessed with next-generation sequencing technologies. Moreover, recent evidences have shown that not only the quantity of tumour mutations, but also their quality may influence response to treatment with ICI. In fact, it seems that clonal heterogeneity of cancer cells, and of predicted neo-antigens, may affect anti-cancer response in patients receiving ICI. Our aim would be to report and discuss the available evidences on this topic along with the techniques used to assess clonal heterogeneity as a biomarker that in future might help physicians to improve NSCLC patients’ selection for immune-oncology treatments.