TGF-β1 potentiates Vγ9Vδ2 T-cell adoptive immunotherapy of cancer

Richard Beatson; Ana Parente Pereira; Leena Halim; Domenico Cozzetto; Caroline Hull; Lynsey Whilding; Olivier Martinez; Chelsea Taylor; Jana Obajdin; Kim Ngan Luu Hoang; Benjamin Draper; Ayesha Iqbal; Tom Hardiman; Tomasz Zabinski; Francis Man; Rafael T. M. de Rosales; Jinger Xie; Fred Aswad; Daniela Achkova; Chung-Yang Ricardo Joseph; Sara  Ciprut; Antonella Adami; Helge Roider; Holger Hess-Stump; Balazs Gyorffy; Jelmar Quist; Anita Grigoriadis; Anette Sommer; Andrew Tutt; John Maher; David Davies

TGF-β1 potentiates Vγ9Vδ2 T-cell adoptive immunotherapy of cancer

Richard Beatson, Ana Parente Pereira, Leena Halim, Domenico Cozzetto, Caroline Hull, Lynsey Whilding, Olivier Martinez, Chelsea Taylor, Jana Obajdin, Kim Ngan Luu Hoang, Benjamin Draper, Ayesha Iqbal, Tom Hardiman, Tomasz Zabinski, Francis Man, Rafael T. M. de Rosales, Jinger Xie, Fred Aswad, Daniela Achkova, Chung-Yang Ricardo JosephSara Ciprut, Antonella Adami, Helge Roider, Holger Hess-Stump, Balazs Gyorffy, Jelmar Quist, Anita Grigoriadis, Anette Sommer, Andrew Tutt, John Maher, David Davies

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Abstract

Despite their role in cancer surveillance, adoptive immunotherapy using γδ T-cells has
achieved limited efficacy. To enhance trafficking to bone marrow, circulating Vγ9Vδ2 T cells are expanded in serum-free medium containing TGF-β1 and IL-2 (γδ[T2] cells) or
medium containing IL-2 alone (γδ[2] cells, as the control). Unexpectedly, the yield and
viability of γδ[T2] cells are also increased by TGF-β1, when compared to γδ[2]
controls. γδ[T2] cells are less differentiated and yet display increased cytolytic activity,
cytokine release and anti-tumor activity in several leukemic and solid tumor
models. Efficacy is further enhanced by cancer cell sensitization using
aminobisphosphonates or Ara-C. A number of contributory effects of TGF-β were
identified, including prostaglandin E 2 receptor downmodulation, TGF-β insensitivity
and upregulated integrin activity. Biological relevance is supported by the identification of a favorable γδ[T2] signature in acute myeloid leukemia (AML). Given their enhanced therapeutic activity and compatibility with allogeneic use, γδ[T2] cells warrant evaluation in cancer immunotherapy.

Original language	English
Journal	Cell Reports Medicine
Publication status	Accepted/In press - 18 Nov 2021

Keywords

Gamma delta T-cell,
TGF-b,
acute myeloid leukemia,
prostaglandin E2,
aminobisphosphonate,
Ara-C

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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CR-MEDICINE-D-21-00223_R3Licence: CC BY

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Beatson, R., Parente Pereira, A., Halim, L., Cozzetto, D., Hull, C., Whilding, L., Martinez, O., Taylor, C., Obajdin, J., Luu Hoang, K. N., Draper, B., Iqbal, A., Hardiman, T., Zabinski, T., Man, F., T. M. de Rosales, R., Xie, J., Aswad, F., Achkova, D., ... Davies, D. (Accepted/In press). TGF-β1 potentiates Vγ9Vδ2 T-cell adoptive immunotherapy of cancer. Cell Reports Medicine.

@article{1b4d0114ea7748b09aa6b36f3aa0bee1,

title = "TGF-β1 potentiates Vγ9Vδ2 T-cell adoptive immunotherapy of cancer",

abstract = "Despite their role in cancer surveillance, adoptive immunotherapy using γδ T-cells hasachieved limited efficacy. To enhance trafficking to bone marrow, circulating Vγ9Vδ2 T cells are expanded in serum-free medium containing TGF-β1 and IL-2 (γδ[T2] cells) ormedium containing IL-2 alone (γδ[2] cells, as the control). Unexpectedly, the yield andviability of γδ[T2] cells are also increased by TGF-β1, when compared to γδ[2]controls. γδ[T2] cells are less differentiated and yet display increased cytolytic activity,cytokine release and anti-tumor activity in several leukemic and solid tumormodels. Efficacy is further enhanced by cancer cell sensitization usingaminobisphosphonates or Ara-C. A number of contributory effects of TGF-β wereidentified, including prostaglandin E 2 receptor downmodulation, TGF-β insensitivityand upregulated integrin activity. Biological relevance is supported by the identification of a favorable γδ[T2] signature in acute myeloid leukemia (AML). Given their enhanced therapeutic activity and compatibility with allogeneic use, γδ[T2] cells warrant evaluation in cancer immunotherapy.",

keywords = "Gamma delta T-cell,, TGF-b,, acute myeloid leukemia,, prostaglandin E2,, aminobisphosphonate,, Ara-C",

author = "Richard Beatson and {Parente Pereira}, Ana and Leena Halim and Domenico Cozzetto and Caroline Hull and Lynsey Whilding and Olivier Martinez and Chelsea Taylor and Jana Obajdin and {Luu Hoang}, {Kim Ngan} and Benjamin Draper and Ayesha Iqbal and Tom Hardiman and Tomasz Zabinski and Francis Man and {T. M. de Rosales}, Rafael and Jinger Xie and Fred Aswad and Daniela Achkova and {Ricardo Joseph}, Chung-Yang and Sara Ciprut and Antonella Adami and Helge Roider and Holger Hess-Stump and Balazs Gyorffy and Jelmar Quist and Anita Grigoriadis and Anette Sommer and Andrew Tutt and John Maher and David Davies",

year = "2021",

month = nov,

day = "18",

language = "English",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

}

Beatson, R , Parente Pereira, A , Halim, L, Cozzetto, D, Hull, C , Whilding, L , Martinez, O, Taylor, C, Obajdin, J, Luu Hoang, KN, Draper, B, Iqbal, A, Hardiman, T , Zabinski, T, Man, F, T. M. de Rosales, R, Xie, J, Aswad, F, Achkova, D, Ricardo Joseph, C-Y, Ciprut, S, Adami, A, Roider, H, Hess-Stump, H, Gyorffy, B, Quist, J , Grigoriadis, A, Sommer, A, Tutt, A , Maher, J & Davies, D 2021, 'TGF-β1 potentiates Vγ9Vδ2 T-cell adoptive immunotherapy of cancer', Cell Reports Medicine.

TY - JOUR

T1 - TGF-β1 potentiates Vγ9Vδ2 T-cell adoptive immunotherapy of cancer

AU - Beatson, Richard

AU - Parente Pereira, Ana

AU - Halim, Leena

AU - Cozzetto, Domenico

AU - Hull, Caroline

AU - Whilding, Lynsey

AU - Martinez, Olivier

AU - Taylor, Chelsea

AU - Obajdin, Jana

AU - Luu Hoang, Kim Ngan

AU - Draper, Benjamin

AU - Iqbal, Ayesha

AU - Hardiman, Tom

AU - Zabinski, Tomasz

AU - Man, Francis

AU - T. M. de Rosales, Rafael

AU - Xie, Jinger

AU - Aswad, Fred

AU - Achkova, Daniela

AU - Ricardo Joseph, Chung-Yang

AU - Ciprut, Sara

AU - Adami, Antonella

AU - Roider, Helge

AU - Hess-Stump, Holger

AU - Gyorffy, Balazs

AU - Quist, Jelmar

AU - Grigoriadis, Anita

AU - Sommer, Anette

AU - Tutt, Andrew

AU - Maher, John

AU - Davies, David

PY - 2021/11/18

Y1 - 2021/11/18

N2 - Despite their role in cancer surveillance, adoptive immunotherapy using γδ T-cells hasachieved limited efficacy. To enhance trafficking to bone marrow, circulating Vγ9Vδ2 T cells are expanded in serum-free medium containing TGF-β1 and IL-2 (γδ[T2] cells) ormedium containing IL-2 alone (γδ[2] cells, as the control). Unexpectedly, the yield andviability of γδ[T2] cells are also increased by TGF-β1, when compared to γδ[2]controls. γδ[T2] cells are less differentiated and yet display increased cytolytic activity,cytokine release and anti-tumor activity in several leukemic and solid tumormodels. Efficacy is further enhanced by cancer cell sensitization usingaminobisphosphonates or Ara-C. A number of contributory effects of TGF-β wereidentified, including prostaglandin E 2 receptor downmodulation, TGF-β insensitivityand upregulated integrin activity. Biological relevance is supported by the identification of a favorable γδ[T2] signature in acute myeloid leukemia (AML). Given their enhanced therapeutic activity and compatibility with allogeneic use, γδ[T2] cells warrant evaluation in cancer immunotherapy.

AB - Despite their role in cancer surveillance, adoptive immunotherapy using γδ T-cells hasachieved limited efficacy. To enhance trafficking to bone marrow, circulating Vγ9Vδ2 T cells are expanded in serum-free medium containing TGF-β1 and IL-2 (γδ[T2] cells) ormedium containing IL-2 alone (γδ[2] cells, as the control). Unexpectedly, the yield andviability of γδ[T2] cells are also increased by TGF-β1, when compared to γδ[2]controls. γδ[T2] cells are less differentiated and yet display increased cytolytic activity,cytokine release and anti-tumor activity in several leukemic and solid tumormodels. Efficacy is further enhanced by cancer cell sensitization usingaminobisphosphonates or Ara-C. A number of contributory effects of TGF-β wereidentified, including prostaglandin E 2 receptor downmodulation, TGF-β insensitivityand upregulated integrin activity. Biological relevance is supported by the identification of a favorable γδ[T2] signature in acute myeloid leukemia (AML). Given their enhanced therapeutic activity and compatibility with allogeneic use, γδ[T2] cells warrant evaluation in cancer immunotherapy.

KW - Gamma delta T-cell,

KW - TGF-b,

KW - acute myeloid leukemia,

KW - prostaglandin E2,

KW - aminobisphosphonate,

KW - Ara-C

M3 - Article

SN - 2666-3791

JO - Cell Reports Medicine

JF - Cell Reports Medicine

ER -

TGF-β1 potentiates Vγ9Vδ2 T-cell adoptive immunotherapy of cancer

Abstract

Keywords

UN SDGs

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