Immunogenomic, single-cell and spatial dissection of CD8+T cell exhaustion reveals critical determinants of cancer immunotherapy

Naulaerts, S.; Borras, D. M.; Martinez, A. A.; Messiaen, J.; Van Herck, Y.; Gelens, L.; Venken, T.; Vanmeerbeek, I.; More, S.; Sprooten, J.; Bechter, O.; Bergers, G.; Liston, A.; De Vleeschouwer, S.; Van den Eynde, B. J.; Lambrechts, D.; Borst, J.; Bosisio, F. M.; Tejpar, S.; De Smet, F.; Garg, A. D.

doi:10.1101/2021.11.22.468617

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bioRxiv · 10.1101/2021.11.22.468617

Immunogenomic, single-cell and spatial dissection of CD8+T cell exhaustion reveals critical determinants of cancer immunotherapy

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Abstract

Tumoural-CD8+T cells exhibit exhausted or dysfunctional states. Contrary to immunotherapy-responsive exhausted-CD8+T cells, the clinical features of dysfunctional-CD8+T cells are disputed. Hence, we conducted large-scale multi-omics and multi-dimensional mapping of CD8+T cell-states across multiple cancer patient-cohorts. This identified tumour-specific continuum of CD8+T cell-states across 6 human cancers, partly imprinted by organ-specific immuno-modulatory niches. Herein, melanoma and glioblastoma enriched prototypical exhausted (CD8+TEXT) and severely-dysfunctional (CD8+TSDF) states, respectively. Contrary to CD8+TEXT, CD8+TSDF displayed transcriptomic and epigenetic effector/cytolytic dysfunctions, and dysregulated effector/memory single-cell trajectories, culminating into maladaptive prodeath stress and cell-cycle defects. Suboptimal antigen-priming underscored CD8+TSDF, which was distinct from immune-checkpoints "rich" CD8+TEXT, reflecting chronic antigen-stimulation. Continuum variation also existed on tumour spatial-level, with convergent (CD8+TEXT-supportive vascular regions) and divergent features (dysfunctional CD4+T::CD8+TSDFcell-to-cell interactions) between melanoma and glioblastoma. Globally, IFN{gamma}-IL2 disparities, paucity of intra-tumoural CD4+/CD8+T cells, and myeloid TGF{beta}/wound healing responses, distinguished CD8+TSDF-landscape. Within immuno-oncology clinical-trials, anti-PD1 immunotherapy failed to "reinvigorate" CD8+TSDF-landscape, and instead facilitated effector-dysfunction and TGF{beta}/wound healing. However, cellular immunotherapies (dendritic cell-vaccines, adoptive T-cell therapy) ameliorated assorted CD8+TSDF-landscape disparities, highlighting a roadmap for anti-glioblastoma multimodal-immunotherapy. Collectively, our study comprehensively expands clinical-knowledge on CD8+T cell-exhaustion and suggests that tumour-specific, pre-existing CD8+TEXT/TSDF-states, determine immunotherapy-responses.

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Naulaerts, S., Borras, D. M., Martinez, A. A., Messiaen, J., Van Herck, Y., Gelens, L., Venken, T., Vanmeerbeek, I., More, S., Sprooten, J., Bechter, O., Bergers, G., Liston, A., De Vleeschouwer, S., Van den Eynde, B. J., Lambrechts, D., Borst, J., Bosisio, F. M., Tejpar, S., De Smet, F., Garg, A. D.. 2021-11-22. Immunogenomic, single-cell and spatial dissection of CD8+T cell exhaustion reveals critical determinants of cancer immunotherapy. https://doi.org/10.1101/2021.11.22.468617

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