Immunosuppressive TGF-β1 and the genes associated with TGF-β1 activation were highly expressed in many tumors. Cells expressing high levels of TGF-β1 co-localized with immune cells in tumors, and IFNγ expression was low in these areas. In vitro, the addition of TGF-β1 activated immunosuppressive pathways that inhibited both proliferative and cytotoxic responses of T cells engineered to express tumor-specific TCRs. T cells co-expressing a dominant-negative form of the TGFβRII subunit of the TGFβ receptor ablated TGF-β1 signaling and retained proliferative, cytokine production, and cytotoxic responses, even in the presence of TGF-β1.
Contributed by Margot O’Toole
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.
Author Info: (1) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom; jonathan.silk@enarabio.com joanna.brewer@adaptimmune.com. (2) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom.
Author Info: (1) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom; jonathan.silk@enarabio.com joanna.brewer@adaptimmune.com. (2) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (3) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (4) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (5) Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and. (6) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (7) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (8) Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and. (9) Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and. (10) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (11) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (12) Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and. (13) Cell and Gene Therapy Product Development and Supply, Analytical Development, GlaxoSmithKline, Collegeville, PA. (14) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (15) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (16) Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and. (17) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (18) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (19) Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and. (20) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (21) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (22) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (23) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (24) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (25) Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and. (26) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom. (27) Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom; jonathan.silk@enarabio.com joanna.brewer@adaptimmune.com.
