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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

Genes & Immunity volume 22, pages 108–119 (2021)Cite this article

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A Correction to this article was published on 01 December 2022

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Abstract

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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Acknowledgements

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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  1. These authors contributed equally: Isaure Vanmeerbeek, Daniel M. Borras, Jenny Sprooten

Authors and Affiliations

  1. Laboratory of Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium

    Isaure Vanmeerbeek, Daniel M. Borras, Jenny Sprooten & Abhishek D. Garg

  2. Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium

    Oliver Bechter

  3. Department of General Medical Oncology, UZ Leuven, Leuven, Belgium

    Oliver Bechter

  4. Laboratory for Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium

    Sabine Tejpar

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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). https://doi.org/10.1038/s41435-021-00138-4

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