OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs Journal Article
| Authors: | Yang, N.; Wang, Y.; Liu, S.; Baseer Tariq, S.; Luna, J. M.; Mazo, G.; Tan, A.; Zhang, T.; Wang, J.; Yan, W.; Choi, J.; Rossi, A.; Xiang, J. Z.; Rice, C. M.; Merghoub, T.; Wolchok, J. D.; Deng, L. |
| Article Title: | OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs |
| Abstract: | Effective depletion of immune suppressive regulatory T cells (Tregs) in the tumor microenvironment without triggering systemic autoimmunity is an important strategy for cancer immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus with a long history of human use. Here, we report rational engineering of an immune-activating recombinant MVA (rMVA, MVA∆E5R-Flt3L-OX40L) with deletion of the vaccinia E5R gene (encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase, cGAS) and expression of two membrane-anchored transgenes, Flt3L and OX40L. Intratumoral (IT) delivery of rMVA (MVA∆E5R-Flt3L-OX40L) generates potent antitumor immunity, dependent on CD8+ T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and type I IFN signaling. Remarkably, IT rMVA (MVA∆E5R-Flt3L-OX40L) depletes OX40hi regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Single-cell RNA-seq analyses of tumors treated with rMVA showed the depletion of OX40hiCCR8hi Tregs and expansion of IFN-responsive Tregs. Taken together, our study provides a proof-of-concept for depleting and reprogramming intratumoral Tregs via an immune-activating rMVA. © 2023 Yang et al. |
| Keywords: | genetics; neoplasm; neoplasms; cd8+ t lymphocyte; cd8-positive t-lymphocytes; vaccinia virus; nucleotidyltransferase; tumor microenvironment; nucleotidyltransferases; humans; human; modified vaccinia ankara virus |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 220 |
| Issue: | 8 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2023-08-07 |
| Start Page: | e20221166 |
| Language: | English |
| DOI: | 10.1084/jem.20221166 |
| PUBMED: | 37145142 |
| PROVIDER: | scopus |
| PMCID: | PMC10165539 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Liang Deng -- Export Date: 1 June 2023 -- Source: Scopus |
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