Key Points
Active TGF-β is present in many cancer indications.
dnTGFβRII can be coexpressed in T cells with engineered TCRs.
dnTGFβRII–expressing T cells are resistant to inhibition by TGF-β.
Abstract
Adoptive T cell therapy with T cells expressing affinity-enhanced TCRs has shown promising results in phase 1/2 clinical trials for solid and hematological tumors. However, depth and durability of responses to adoptive T cell therapy can suffer from an inhibitory tumor microenvironment. A common immune-suppressive agent is TGF-β, which is secreted by tumor cells and cells recruited to the tumor. We investigated whether human T cells could be engineered to be resistant to inhibition by TGF-β. Truncating the intracellular signaling domain from TGF-β receptor (TGFβR) II produces a dominant-negative receptor (dnTGFβRII) that dimerizes with endogenous TGFβRI to form a receptor that can bind TGF-β but cannot signal. We previously generated specific peptide enhanced affinity receptor TCRs recognizing the HLA-A*02–restricted peptides New York esophageal squamous cell carcinoma 1 (NY-ESO-1)157–165/l-Ag family member-1A (TCR: GSK3377794, formerly NY-ESO-1c259) and melanoma Ag gene A10254–262 (TCR: ADP-A2M10, formerly melanoma Ag gene A10c796). In this article, we show that exogenous TGF-β inhibited in vitro proliferation and effector functions of human T cells expressing these first-generation high-affinity TCRs, whereas inhibition was reduced or abolished in the case of second-generation TCRs coexpressed with dnTGFβRII (e.g., GSK3845097). TGF-β isoforms and a panel of TGF-β–associated genes are overexpressed in a range of cancer indications in which NY-ESO-1 is commonly expressed, particularly in synovial sarcoma. As an example, immunohistochemistry/RNAscope identified TGF-β–positive cells close to T cells in tumor nests and stroma, which had low frequencies of cells expressing IFN-γ in a non–small cell lung cancer setting. Coexpression of dnTGFβRII may therefore improve the efficacy of TCR-transduced T cells.
This article is featured in Top Reads, p.
Footnotes
This work was supported by Adaptimmune and GlaxoSmithKline.
A.D.B. conceived the project. J.D.S., K.J.A., T.V.C., K.L.C., J.J., C.O., D.J.F., A.P., L.P., C.E.P., L.L.Q., A.G.R., M.S., D.S., B.T., G.E.W., and R.W. performed experiments. A.D.B., A.Q., and P.V. provided key reagents. J.D.S., R.J.M.A., K.J.A., A.D.B., S.B., T.V.C., K.L.C., C.O., D.J.F., A.P., L.L.Q., M.S., J.P.S., B.T., G.E.W., R.W., B.K.J., C.M.B., A.B.G., and J.E.B. contributed to the conception and design of the studies. J.D.S., R.J.M.A., and S.B. prepared the manuscript. A.D.B., J.P.S., C.M.B., A.B.G., J.E.B., and K.L.C. provided critical review.
The online version of this article contains supplemental material.
Abbreviations used in this article
- ACT
- adoptive T cell therapy
- AUC
- area under the curve
- CTS
- Cell Therapy Systems
- 3D
- three-dimensional
- dnTGFβRII
- dominant-negative TGF-β receptor II
- FPKM
- fragments per kilobase million
- GZMB
- granzyme B
- IHC
- immunohistochemistry
- ISH
- in situ hybridization
- LAGE
- l-Ag-family member
- LUAD
- lung adenocarcinoma
- MAGE
- melanoma Ag gene
- MFI
- median fluorescence intensity
- NSCLC
- non–small cell lung cancer
- NTD
- nontransduced
- NY-ESO-1
- New York esophageal squamous cell carcinoma 1
- PD-L1
- programmed death-ligand 1
- PPIB
- peptidylprolyl isomerase B
- rhIL-2
- recombinant human IL-2
- SARC
- synovial sarcoma
- SMAD
- similar to mothers against decapentaplegic
- TCGA
- The Cancer Genome Atlas
- TGFβR
- TGF-β receptor
- TNFR
- TNF receptor
- Treg
- regulatory T cell
- Vβ
- β-chain V region
- Received December 2, 2020.
- Accepted October 20, 2021.
- Copyright © 2021 by The American Association of Immunologists, Inc.
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$37.50
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.