Early memory differentiation and cell death resistance in T cells predicts melanoma response to sequential anti-CTLA4 and anti-PD1 immunotherapy (vol 22, pg 108, 2021)

Immune checkpoint blockers (ICBs)-based immunotherapy has revolutionised oncology. However, the benefits of ICBs are limited to only a subset of patients. Herein, the biomarkers-driven application of ICBs promises to increase their efficacy. Such biomarkers include lymphocytic IFN gamma-signalling and/or cytolytic activity (granzymes and perforin-1) footprints, whose levels in pretreatment tumours can predict favourable patient survival following ICB-treatment. However, it is not clear whether such biomarkers have the same value in predicting survival of patients receiving first-line anti-CTLA4 ICB-therapy, and subsequently anti-PD1 ICBtherapy (i.e., sequential ICB-immunotherapy regimen). To address this, we applied highly integrated systems/computational immunology approaches to existing melanoma bulk-tumour transcriptomic and single-cell (sc)RNAseq data originating from immunooncology clinical studies applying ICB-treatment. Interestingly, we observed that CD8+/CD4+T cell-associated IFN gamma-signalling orcytolytic activity signatures fail to predict tumour response inpatients treated with anti-CTLA4 ICB-therapy as afirst-line and anti-PD1 ICB-therapy in the second-line setting. On the contrary,signatures associated with early memory CD8+/CD4+T cells(integrating TCF1-driven stem-like transcriptional programme),capable of resisting cell death/apoptosis, better predicted objectiveresponse rates to ICB-immunotherapy, and favourable survival inthe setting of sequential ICB-immunotherapy. These observationssuggest that sequencing of ICB-therapy might have a specificimpact on the T cell-repertoire and may influence the predictivevalue of tumoural immune biomarkers.