Interferon-gamma gene signature (T-cell-inflamed signature)

What is measured: RNA expression of interferon-gamma-responsive and T-cell genes such as IFNG, CXCL9, CXCL10, CXCL11, IDO1, STAT1, HLA-DRA, PRF1, GZMB and CD8A. How: NanoString or RNA sequencing of tumour tissue; the 18-gene T-cell-inflamed gene expression profile of Ayers and colleagues (2017) was derived in pembrolizumab-treated patients and correlates with PD-L1 immunohistochemistry and tumour-infiltrating lymphocytes but adds to tumour mutational burden, the two being largely independent (Cristescu, Science 2018). A high score tracks higher response rates and longer progression-free survival to pembrolizumab across the KEYNOTE programme and to nivolumab with ipilimumab in melanoma; in the neoadjuvant NADINA trial almost every patient with a high score had a major pathological response and could skip adjuvant therapy. What a result changes: nothing in routine care yet; it stratifies trials, defines biomarker-guided arms (including follow-on trials that adapt adjuvant therapy to the score), and identifies cold tumours for combination strategies; it does not predict benefit from chemotherapy or anti-VEGF drugs. Where it matters: melanoma, advanced and stage III.