PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

Daniel Davies; Shraddha Kamdar; Richard Woolf; Iva Zlatareva; Maria Luisa Iannitto; Cienne Morton; Yasmin Haque; Hannah Martin; Dhruva Biswas; Susan Ndagire; Martina Munonyara; Cheryl Gillett; Olga O’Neill; Oliver Nussbaumer; Adrian Hayday; Yin Wu

doi:10.1038/s43018-023-00690-0

PD-1 defines a distinct, functional, tissue-adapted state in Vδ1⁺ T cells with implications for cancer immunotherapy

Daniel Davies, Shraddha Kamdar, Richard Woolf, Iva Zlatareva, Maria Luisa Iannitto, Cienne Morton, Yasmin Haque, Hannah Martin, Dhruva Biswas, Susan Ndagire, Martina Munonyara, Cheryl Gillett, Olga O’Neill, Oliver Nussbaumer, Adrian Hayday^*, Yin Wu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1⁺ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1⁺ cells, we show that PD-1⁺Vδ1⁺ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1⁺CD8⁺ αβ T cells. In particular, PD-1⁺Vδ1⁺ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.

Original language	English
Pages (from-to)	420-432
Number of pages	13
Journal	Nature Cancer
Volume	5
Issue number	3
DOIs	https://doi.org/10.1038/s43018-023-00690-0
Publication status	Published - Mar 2024

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10.1038/s43018-023-00690-0

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Davies, D., Kamdar, S., Woolf, R., Zlatareva, I., Iannitto, M. L., Morton, C., Haque, Y., Martin, H., Biswas, D., Ndagire, S., Munonyara, M., Gillett, C., O’Neill, O., Nussbaumer, O., Hayday, A., & Wu, Y. (2024). PD-1 defines a distinct, functional, tissue-adapted state in Vδ1⁺ T cells with implications for cancer immunotherapy. Nature Cancer, 5(3), 420-432. https://doi.org/10.1038/s43018-023-00690-0

@article{9405de07843541869e58960647bd0116,

title = "PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy",

abstract = "Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αβ T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.",

author = "Daniel Davies and Shraddha Kamdar and Richard Woolf and Iva Zlatareva and Iannitto, {Maria Luisa} and Cienne Morton and Yasmin Haque and Hannah Martin and Dhruva Biswas and Susan Ndagire and Martina Munonyara and Cheryl Gillett and Olga O{\textquoteright}Neill and Oliver Nussbaumer and Adrian Hayday and Yin Wu",

note = "Funding Information: We thank F. Cahill, A. Haire, H. Wylie, D. Marsh and J. Farhadi for consenting and recruiting the patients and for the acquisition of the excess skin samples. We thank the King{\textquoteright}s Health Partners Cancer Biobank for supplying the primary tumor tissue from patients with NSCLC. We thank P. Vantourout for helpful advice and discussions and E. Theodoridis for logistical support. A.H. received support from the Francis Crick Institute, which receives core funding from Cancer Research UK (grant no. FC001093), the Medical Research Council (MRC) (grant no. FC001093) and the Wellcome Trust (grant no. FC001093). R.W. was supported by an MRC predoctoral fellowship (MR/K002627/1). D.B. was supported by funding from the Idea to Innovation (i2i) Crick translation scheme, the MRC and the University College London Hospitals NHS Foundation Trust Biomedical Research Centre. O.N. and I.Z. were supported by the Guy{\textquoteright}s and St Thomas{\textquoteright} Hospital Trust Biomedical Research Centre. D.D., S.K. and M.L.I. were supported by a sponsored research agreement with Gamma Delta Therapeutics. Y.W. was supported by funding from the Wellcome Trust (220589/Z/20/Z). Figure and Extended Data Fig. were created with BioRender.com . Funding Information: D.D., S.K. and M.L.I. were previously employed on a sponsored research agreement with Gamma Delta Therapeutics. D.D. and S.K. are currently employed on a sponsored research agreement with Takeda Pharmaceuticals (starting in February 2023). I.Z. was previously employed on a sponsored research agreement with Takeda Pharmaceuticals (February–July 2023). D.B. reports personal fees from NanoString and AstraZeneca and has a patent (PCT/GB2020/050221) issued on methods for cancer prognostication. A.H. receives laboratory research funding from Takeda Pharmaceuticals (starting in February 2023) and consults for eGenesis and Prokarium. Y.W. consults for PersonGen Biotherapeutics and E15 VC. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = mar,

doi = "10.1038/s43018-023-00690-0",

language = "English",

volume = "5",

pages = "420--432",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Nature Research",

number = "3",

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Davies, D, Kamdar, S , Woolf, R , Zlatareva, I, Iannitto, ML, Morton, C, Haque, Y, Martin, H, Biswas, D, Ndagire, S, Munonyara, M, Gillett, C, O’Neill, O, Nussbaumer, O, Hayday, A & Wu, Y 2024, 'PD-1 defines a distinct, functional, tissue-adapted state in Vδ1⁺ T cells with implications for cancer immunotherapy', Nature Cancer, vol. 5, no. 3, pp. 420-432. https://doi.org/10.1038/s43018-023-00690-0

TY - JOUR

T1 - PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

AU - Davies, Daniel

AU - Kamdar, Shraddha

AU - Woolf, Richard

AU - Zlatareva, Iva

AU - Iannitto, Maria Luisa

AU - Morton, Cienne

AU - Haque, Yasmin

AU - Martin, Hannah

AU - Biswas, Dhruva

AU - Ndagire, Susan

AU - Munonyara, Martina

AU - Gillett, Cheryl

AU - O’Neill, Olga

AU - Nussbaumer, Oliver

AU - Hayday, Adrian

AU - Wu, Yin

N1 - Funding Information: We thank F. Cahill, A. Haire, H. Wylie, D. Marsh and J. Farhadi for consenting and recruiting the patients and for the acquisition of the excess skin samples. We thank the King’s Health Partners Cancer Biobank for supplying the primary tumor tissue from patients with NSCLC. We thank P. Vantourout for helpful advice and discussions and E. Theodoridis for logistical support. A.H. received support from the Francis Crick Institute, which receives core funding from Cancer Research UK (grant no. FC001093), the Medical Research Council (MRC) (grant no. FC001093) and the Wellcome Trust (grant no. FC001093). R.W. was supported by an MRC predoctoral fellowship (MR/K002627/1). D.B. was supported by funding from the Idea to Innovation (i2i) Crick translation scheme, the MRC and the University College London Hospitals NHS Foundation Trust Biomedical Research Centre. O.N. and I.Z. were supported by the Guy’s and St Thomas’ Hospital Trust Biomedical Research Centre. D.D., S.K. and M.L.I. were supported by a sponsored research agreement with Gamma Delta Therapeutics. Y.W. was supported by funding from the Wellcome Trust (220589/Z/20/Z). Figure and Extended Data Fig. were created with BioRender.com . Funding Information: D.D., S.K. and M.L.I. were previously employed on a sponsored research agreement with Gamma Delta Therapeutics. D.D. and S.K. are currently employed on a sponsored research agreement with Takeda Pharmaceuticals (starting in February 2023). I.Z. was previously employed on a sponsored research agreement with Takeda Pharmaceuticals (February–July 2023). D.B. reports personal fees from NanoString and AstraZeneca and has a patent (PCT/GB2020/050221) issued on methods for cancer prognostication. A.H. receives laboratory research funding from Takeda Pharmaceuticals (starting in February 2023) and consults for eGenesis and Prokarium. Y.W. consults for PersonGen Biotherapeutics and E15 VC. The remaining authors declare no competing interests. Publisher Copyright: © The Author(s) 2024.

PY - 2024/3

Y1 - 2024/3

N2 - Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αβ T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.

AB - Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αβ T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.

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DO - 10.1038/s43018-023-00690-0

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SN - 2662-1347

VL - 5

SP - 420

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JO - Nature Cancer

JF - Nature Cancer

IS - 3

ER -

PD-1 defines a distinct, functional, tissue-adapted state in Vδ1⁺ T cells with implications for cancer immunotherapy

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