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Early memory differentiation and cell death resistance in T cells predicts melanoma response to sequential anti-CTLA4 and anti-PD1 immunotherapy


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.

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Fig. 1: Systems biology and immunotherapy response-predictive efficacy of lymphocytic effector/cytolytic activity (LECA) signature.
Fig. 2: An overview of the melanoma patient-derived tumour single-cell (sc)RNAseq profiles of infiltrating immune cells.
Fig. 3: LECA-signature’s genes in T single-cells infiltrating melanoma tumours at baseline or during immune checkpoint blockade (ICB) immunotherapy.
Fig. 4: LECA-signature’s genes in T single-cells infiltrating melanoma tumours from immune checkpoint blockade (ICB) immunotherapy responsive or non-responsive patients.
Fig. 5: Differential gene-enrichment analyses in T single-cells infiltrating melanoma tumours from immune checkpoint blockade (ICB) immunotherapy responsive or non-responsive patients.
Fig. 6: Systems biology and immunotherapy response-predictive efficacy of immunotherapy-responsive early memory T-cell signature.


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This study is supported by Research Foundation Flanders (FWO) (Fundamental Research Grant, G0B4620N; Excellence of Science/EOS grant, 30837538, for ‘DECODE’ consortium), KU Leuven (C1 grant, C14/19/098 and POR award funds, POR/16/040), VLIR-UOS (iBOF grant, iBOF/21/048, for ‘MIMICRY’ consortium), and Kom op Tegen Kanker (KOTK/2018/11509/1; and KOTK/2019/11955/1), to ADG. IV is supported by FWO-SB PhD Fellowship (1S06821N). DMB is supported by the Belgian Federation against Cancer grant nos. 2018-127 and 2016-133 and by a grant from Fondation Roi-Baudouin to ST. ST is further supported by a Senior Clinical Investigator award of FWO.

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Vanmeerbeek, I., Borras, D.M., Sprooten, J. et al. Early memory differentiation and cell death resistance in T cells predicts melanoma response to sequential anti-CTLA4 and anti-PD1 immunotherapy. Genes Immun 22, 108–119 (2021).

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