| Title: |
Engineering Cancer Antigen-Specific T Cells to Overcome the Immunosuppressive Effects of TGF-β |
| Authors: |
Silk, Jonathan D; Abbott, Rachel J M; Adams, Katherine J; Bennett, Alan D; Brett, Sara; Cornforth, Terri V; Crossland, Katherine L; Figueroa, David J; Jing, Junping; O’Connor, Caitriona; Pachnio, Annette; Patasic, Lea; Peredo, Carlos E; Quattrini, Adriano; Quinn, Laura L; Rust, Alistair G; Saini, Manoj; Sanderson, Joseph P; Steiner, Dylan; Tavano, Barbara; Viswanathan, Preetha; Wiedermann, Guy E; Wong, Ryan; Jakobsen, Bent K; Britten, Cedrik M; Gerry, Andrew B; Brewer, Joanna E |
| Contributors: |
Adaptimmune Ltd; GlaxoSmithKline |
| Source: |
The Journal of Immunology ; volume 208, issue 1, page 169-180 ; ISSN 0022-1767 1550-6606 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2022 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.4049/jimmunol.2001357 |
| Availability: |
https://doi.org/10.4049/jimmunol.2001357; https://academic.oup.com/jimmunol/article-pdf/208/1/169/61189867/ji2001357.pdf |
| Rights: |
https://academic.oup.com/pages/standard-publication-reuse-rights |
| Accession Number: |
edsbas.2C7470C1 |
| Database: |
BASE |