An oncolytic virus-delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment.

Autor:	DePeaux K; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Rivadeneira DB; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Lontos K; Stem Cell Transplantation and Cellular Therapy Center, The University of Texas, MD Anderson Cancer Center , Houston, TX, USA., Dean VG; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Gunn WG; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Watson MJ; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Yao T; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Wilfahrt D; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Hinck C; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Wieteska L; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Thorne SH; Kalivir Immunotherapeutics , Pittsburgh, PA, USA., Hinck AP; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Delgoffe GM; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2023 Oct 02; Vol. 220 (10). Date of Electronic Publication: 2023 Aug 08.
DOI:	10.1084/jem.20230053
Abstrakt:	While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing immune infiltration and preventing immunosuppression are of critical need. We previously generated αPD-1 resistant variants of the murine HNSCC model MEER. While entirely αPD-1 resistant, these tumors regress after single dose of oncolytic vaccinia virus (VV). We then generated a VV-resistant MEER line to dissect the immunologic features of sensitive and resistant tumors. While treatment of both tumor types induced immune infiltration and IFNγ, we found a defining feature of resistance was elevation of immunosuppressive cytokines like TGFβ, which blunted IFNγ signaling, especially in regulatory T cells. We engineered VV to express a genetically encoded TGFβRII inhibitor. Inhibitor-expressing VV produced regressions in resistant tumor models and showed impressive synergy with checkpoint blockade. Importantly, tumor-specific, viral delivery of TGFβ inhibition had no toxicities associated with systemic TGFβ/TGFβR inhibition. Our data suggest that aside from stimulating immune infiltration, oncolytic viruses are attractive means to deliver agents to limit immunosuppression in cancer. (© 2023 DePeaux et al.)
Databáze:	MEDLINE
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