biostudies-literatureDePeaux KNIAID NIH HHSNational Institutes of HealthAlliance for Cancer Gene TherapyNational Institute of General Medical SciencesCancer Research InstituteUniversity of Pittsburgh Medical CenterStand Up to CancerHillman Fellows for Innovative Cancer Research ProgramMark Foundation For Cancer ResearchNational Cancer InstituteNCI NIH HHSNIGMS NIH HHSAmerican Association for Cancer Researche20230053https://www.ebi.ac.uk/biostudies/studies/S-EPMC10407786biostudies-literatureUnknown220(10)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 encodThe Journal of experimental medicineAn oncolytic virus-delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment.PMC10407786GM58670DP2 AI136598P30CA047904DP2AI136598SU2C-AACR-IRG-04-16T32-CA082084P50CA097190R01 GM058670R01 AI171483R01 CA233622F31-CA247129P50 CA121973R01AI171483P30 CA047904P50 CA097190P50CA121973T32 CA082084F31 CA247129T32 AI089443CA233622Lontos KGunn WGThorne SHWieteska LHinck APDePeaux KWatson MJYao TDean VGDelgoffe GMWilfahrt DHinck CRivadeneira DBfalseAn oncolytic virus-delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment.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 encod2023-01-01T00:00:00Z2023 Oct2026-04-29T02:25:47.804Z2025-04-21T15:03:02.735ZS-EPMC104077863755247510.1084/jem.20230053