| First Author | DePeaux K | Year | 2023 |
| Journal | J Exp Med | Volume | 220 |
| Issue | 10 | PubMed ID | 37552475 |
| Mgi Jnum | J:340852 | Mgi Id | MGI:7518178 |
| Doi | 10.1084/jem.20230053 | Citation | DePeaux K, et al. (2023) An oncolytic virus-delivered TGFbeta inhibitor overcomes the immunosuppressive tumor microenvironment. J Exp Med 220(10) |
| abstractText | 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 alphaPD-1 resistant variants of the murine HNSCC model MEER. While entirely alphaPD-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 IFNgamma, we found a defining feature of resistance was elevation of immunosuppressive cytokines like TGFbeta, which blunted IFNgamma signaling, especially in regulatory T cells. We engineered VV to express a genetically encoded TGFbetaRII inhibitor. Inhibitor-expressing VV produced regressions in resistant tumor models and showed impressive synergy with checkpoint blockade. Importantly, tumor-specific, viral delivery of TGFbeta inhibition had no toxicities associated with systemic TGFbeta/TGFbetaR inhibition. Our data suggest that aside from stimulating immune infiltration, oncolytic viruses are attractive means to deliver agents to limit immunosuppression in cancer. |
