TGF-β1 potentiates Vγ9Vδ2 T cell adoptive immunotherapy of cancer

Richard E. Beatson; Ana C. Parente-Pereira; Leena Halim; Domenico Cozzetto; Caroline Hull; Lynsey M. Whilding; Olivier Martinez; Chelsea A. 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 G. Roider; Holger Hess-Stumpp; Balázs Győrffy; Jelmar Quist; Anita Grigoriadis; Anette Sommer; Andrew N.J. Tutt; David M. Davies; John Maher

doi:10.1016/j.xcrm.2021.100473

TGF-β1 potentiates Vγ9Vδ2 T cell adoptive immunotherapy of cancer

Richard E. Beatson, Ana C. Parente-Pereira, Leena Halim, Domenico Cozzetto, Caroline Hull, Lynsey M. Whilding, Olivier Martinez, Chelsea A. 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 G. Roider, Holger Hess-Stumpp, Balázs Győrffy, Jelmar Quist, Anita Grigoriadis, Anette Sommer, Andrew N.J. Tutt, David M. Davies, John Maher^*

^*Corresponding author for this work

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

21 Citations (Scopus)

Abstract

Despite its 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 antitumor 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 are described, including prostaglandin E₂ 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
Article number	100473
Journal	Cell Reports Medicine
Volume	2
Issue number	12
DOIs	https://doi.org/10.1016/j.xcrm.2021.100473
Publication status	Published - 21 Dec 2021

Keywords

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

UN SDGs

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

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10.1016/j.xcrm.2021.100473

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Beatson, R. E., Parente-Pereira, A. C., Halim, L., Cozzetto, D., Hull, C., Whilding, L. M., Martinez, O., Taylor, C. A., Obajdin, J., Luu Hoang, K. N., Draper, B., Iqbal, A., Hardiman, T., Zabinski, T., Man, F., de Rosales, R. T. M., Xie, J., Aswad, F., Achkova, D., ... Maher, J. (2021). TGF-β1 potentiates Vγ9Vδ2 T cell adoptive immunotherapy of cancer. Cell Reports Medicine, 2(12), Article 100473. https://doi.org/10.1016/j.xcrm.2021.100473

@article{ed4c136ac990484e988a23df7b1ad654,

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

abstract = "Despite its 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 antitumor 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 are described, including prostaglandin E2 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.",

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

author = "Beatson, {Richard E.} and Parente-Pereira, {Ana C.} and Leena Halim and Domenico Cozzetto and Caroline Hull and Whilding, {Lynsey M.} and Olivier Martinez and Taylor, {Chelsea A.} and Jana Obajdin and {Luu Hoang}, {Kim Ngan} and Benjamin Draper and Ayesha Iqbal and Tom Hardiman and Tomasz Zabinski and Francis Man and {de Rosales}, {Rafael T.M.} and Jinger Xie and Fred Aswad and Daniela Achkova and Joseph, {Chung Yang Ricardo} and Sara Ciprut and Antonella Adami and Roider, {Helge G.} and Holger Hess-Stumpp and Bal{\'a}zs Gy{\H o}rffy and Jelmar Quist and Anita Grigoriadis and Anette Sommer and Tutt, {Andrew N.J.} and Davies, {David M.} and John Maher",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = dec,

day = "21",

doi = "10.1016/j.xcrm.2021.100473",

language = "English",

volume = "2",

journal = "Cell Reports Medicine",

issn = "2666-3791",

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Beatson, RE , Parente-Pereira, AC , Halim, L, Cozzetto, D, Hull, C , Whilding, LM , Martinez, O, Taylor, CA, Obajdin, J, Luu Hoang, KN, Draper, B, Iqbal, A, Hardiman, T , Zabinski, T , Man, F , de Rosales, RTM, Xie, J, Aswad, F, Achkova, D, Joseph, CYR, Ciprut, S, Adami, A, Roider, HG, Hess-Stumpp, H, Győrffy, B, Quist, J , Grigoriadis, A, Sommer, A, Tutt, ANJ , Davies, DM & Maher, J 2021, 'TGF-β1 potentiates Vγ9Vδ2 T cell adoptive immunotherapy of cancer', Cell Reports Medicine, vol. 2, no. 12, 100473. https://doi.org/10.1016/j.xcrm.2021.100473

TY - JOUR

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

AU - Beatson, Richard E.

AU - Parente-Pereira, Ana C.

AU - Halim, Leena

AU - Cozzetto, Domenico

AU - Hull, Caroline

AU - Whilding, Lynsey M.

AU - Martinez, Olivier

AU - Taylor, Chelsea A.

AU - Obajdin, Jana

AU - Luu Hoang, Kim Ngan

AU - Draper, Benjamin

AU - Iqbal, Ayesha

AU - Hardiman, Tom

AU - Zabinski, Tomasz

AU - Man, Francis

AU - de Rosales, Rafael T.M.

AU - Xie, Jinger

AU - Aswad, Fred

AU - Achkova, Daniela

AU - Joseph, Chung Yang Ricardo

AU - Ciprut, Sara

AU - Adami, Antonella

AU - Roider, Helge G.

AU - Hess-Stumpp, Holger

AU - Győrffy, Balázs

AU - Quist, Jelmar

AU - Grigoriadis, Anita

AU - Sommer, Anette

AU - Tutt, Andrew N.J.

AU - Davies, David M.

AU - Maher, John

PY - 2021/12/21

Y1 - 2021/12/21

N2 - Despite its 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 antitumor 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 are described, including prostaglandin E2 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.

AB - Despite its 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 antitumor 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 are described, including prostaglandin E2 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.

KW - acute myeloid leukemia

KW - aminobisphosphonate

KW - Ara-C

KW - Gamma delta T-cell

KW - prostaglandin E2

KW - TGF-β

UR - http://www.scopus.com/inward/record.url?scp=85121521321&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2021.100473

DO - 10.1016/j.xcrm.2021.100473

M3 - Article

C2 - 35028614

AN - SCOPUS:85121521321

SN - 2666-3791

VL - 2

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 12

M1 - 100473

ER -

TGF-β1 potentiates Vγ9Vδ2 T cell adoptive immunotherapy of cancer

Abstract

Keywords

UN SDGs

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