| Autor: |
Vanmeerbeek I; Laboratory of Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium., Borras DM; Laboratory of Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium., Sprooten J; Laboratory of Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium., Bechter O; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.; Department of General Medical Oncology, UZ Leuven, Leuven, Belgium., Tejpar S; Laboratory for Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium., Garg AD; Laboratory of Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. abhishek.garg@kuleuven.be. |
| Abstrakt: |
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 IFNγ-signalling and/or cytolytic activity (granzymes and perforin-1) footprints, whose levels in pre-treatment 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 ICB-therapy (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 immuno-oncology clinical studies applying ICB-treatment. Interestingly, we observed that CD8 + /CD4 + T cell-associated IFNγ-signalling or cytolytic activity signatures fail to predict tumour response in patients treated with anti-CTLA4 ICB-therapy as a first-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 objective response rates to ICB-immunotherapy, and favourable survival in the setting of sequential ICB-immunotherapy. These observations suggest that sequencing of ICB-therapy might have a specific impact on the T cell-repertoire and may influence the predictive value of tumoural immune biomarkers. |
Full text from SpringerLink