Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1

Crowther, Michael D.; Dolton, Garry; Legut, Mateusz; Caillaud, Marine E.; Lloyd, Alun G.; Attaf, Meriem; Galloway, Sarah A. E.; Rius, Cristina; Farrell, Colin; Szomolay, Barbara; Ager, Ann; Parker, Alan L.; Fuller, Anna; Donia, Marco; McCluskey, James; Rossjohn, Jamie; Svane, Inge Marie; Phillips, John D.; Sewell, Andrew K.

doi:10.1038/s41590-019-0578-8

Cited by 210 publications

(250 citation statements)

References 38 publications

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“…TLR agonists have shown synergies and abrogation of suppressive states in vitro [92,93], and cytokines, such as IL-2, could be explored further to evaluate their synergistic effects on effector cell activation and expansion. On the other side, sensory pathways are being discovered which might give additional or alternative therapeutic angles, such as the recently identified MR-1 specific cancer-selective TCR clone [169]. Finally, while there are many hurdles to be jumped, γδ T cells with their high plasticity [27] represent a potential therapeutic option for a significant patient population with solid tumors.…”

Section: Perspectivementioning

confidence: 99%

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Künkele

Wesch

Oberg

et al. 2020

Cells

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Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of Vγ9Vδ2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as γδ Chimeric Antigen Receptor (CAR) -T cells and γδ T-cell engagers are currently under preclinical evaluation. Since the impact of factors, such as the relatively low abundance of γδ T cells within tumor tissue is still under investigation, it remains to be shown whether these effector T cells can provide significant efficacy against solid tumors. Here, we highlight key learnings from the natural role of Vγ9Vδ2 T cells in the elimination of host cells bearing intracellular bacterial agents and we translate these into the setting of tumor therapy. We discuss the availability and relevance of preclinical models as well as currently available tools and knowledge from a drug development perspective. Finally, we compare advantages and disadvantages of existing therapeutic concepts and propose a role for Vγ9Vδ2 T cells in immune-oncology next to Cluster of Differentiation (CD) 3 activating therapies.

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Section: Perspectivementioning

confidence: 99%

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Künkele

Wesch

Oberg

et al. 2020

Cells

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show abstract

“…Unlike classical MHC I, MR1 is not polymorphic in the population and it presents small non-peptidic antigens such as metabolites [42]. A recent study suggests that such MR1-mediated presentation of the metabolome of cancer cells is utilized by specific T cells for ubiquitous cancer targeting [43].…”

Section: Discussionmentioning

confidence: 99%

Sublethal Radiation Affects Antigen Processing and Presentation Genes to Enhance Immunogenicity of Cancer Cells

Punnanitinont

Kannisto

Matsuzaki

et al. 2020

IJMS

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While immunotherapy in cancer is designed to stimulate effector T cell response, tumor-associated antigens have to be presented on malignant cells at a sufficient level for recognition of cancer by T cells. Recent studies suggest that radiotherapy enhances the anti-cancer immune response and also improves the efficacy of immunotherapy. To understand the molecular basis of such observations, we examined the effect of ionizing X-rays on tumor antigens and their presentation in a set of nine human cell lines representing cancers of the esophagus, lung, and head and neck. A single dose of 7.5 or 15 Gy radiation enhanced the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) tumor-antigen-mediated recognition of cancer cells by NY-ESO-1-specific CD8 + T cells. Irradiation led to significant enlargement of live cells after four days, and microscopy and flow cytometry revealed multinucleation and polyploidy in the cells because of dysregulated mitosis, which was also revealed in RNA-sequencing-based transcriptome profiles of cells. Transcriptome analyses also showed that while radiation had no universal effect on genes encoding tumor antigens, it upregulated the expression of numerous genes involved in antigen processing and presentation pathways in all cell lines. This effect may explain the immunostimulatory role of cancer radiotherapy.

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“…They observed regression of leukaemia and prolonged survival of mice. Moreover, Crowther et al demonstrated in in vitro experiments that T cells of melanoma patients transduced with identified TCR could effectively kill not only the patient's own cancer cells, but also non-autologous melanoma cells [159]. These data suggest that the MR1-restricted TCR, recognises diverse types of tumours irrespective of MHC and thus may open the opportunity for a pan-cancer T cell-based therap.…”

Section: Mr1-restricted T Cells-a Novel Population Of T Cells With Pamentioning

confidence: 99%

“…Very recently Crowther and colleagues published results that opened an exciting prospect of potential use of MR1-restricted T cells in immune therapy not limited by MHC polymorphism [159].…”

Section: Mr1-restricted T Cells-a Novel Population Of T Cells With Pamentioning

confidence: 99%

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Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

Chruściel

Urban-Wójciuk

Arcimowicz

et al. 2020

Cancers

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In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of haematologic malignancies, whereas adoptive transfer of autologous tumour infiltrating lymphocytes (TILs) proved to be highly effective in metastatic melanoma. These encouraging results initiated many studies where ACT was tested as a treatment for various solid tumours. In this review, we provide an overview of the challenges of T cell-based immunotherapies of solid tumours. We describe alternative approaches for choosing the most efficient T cells for cancer treatment in terms of their tumour-specificity and phenotype. Finally, we present strategies for improvement of anti-tumour potential of T cells, including combination therapies.

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Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1

Abstract: Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Cited by 210 publications

References 38 publications

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Sublethal Radiation Affects Antigen Processing and Presentation Genes to Enhance Immunogenicity of Cancer Cells

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

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