To induce local antitumor immunity and deplete tumor-infiltrating Tregs, Yang and Wang et al. engineered the modified vaccinia virus Ankara (MVA) with a deletion of the vaccinia E5R gene (an inhibitor of the cGAS/STING pathway) and insertion of transgenes for surface-bound Flt3L and OX40L expression (rMVA). Intratumoral delivery of rMVA in mouse models delayed tumor growth and increased survival. Therapy induced CD8+ and CD4+ T cell activation and reduced the highly suppressive tumoral OX40hi Treg subset. Efficacy was T cell-dependent and improved with anti-PD-L1 cotreatment. A human version (rhMVA) activated T cells and reduced Tregs ex vivo in human Paget’s disease skin biopsies.
Contributed by Maartje Wouters
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, MVAÆE5R-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 (MVAÆE5R-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 (MVAÆE5R-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.
Author Info: (1) Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ROR: https://ror.org/02yrq0923 (2) Department of Medicine, Dermatology S
Author Info: (1) Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ROR: https://ror.org/02yrq0923 (2) Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ROR: https://ror.org/02yrq0923 (3) Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ROR: https://ror.org/02yrq0923 (4) Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ROR: https://ror.org/02yrq0923 (5) The Laboratory of Virology and Infectious Disease, The Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125 (6) Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ROR: https://ror.org/02yrq0923 (7) Genomic Resources Core Facility, Weill Cornell Medical College , New York, NY, USA. ROR: https://ror.org/02r109517 (8) Genomic Resources Core Facility, Weill Cornell Medical College , New York, NY, USA. ROR: https://ror.org/02r109517 (9) Genvira Biosciences , Ottawa, Canada. (10) IMVAQ Therapeutics , Sammamish, WA, USA. (11) IMVAQ Therapeutics , Sammamish, WA, USA. (12) Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ROR: https://ror.org/02yrq0923 (13) Genomic Resources Core Facility, Weill Cornell Medical College , New York, NY, USA. ROR: https://ror.org/02r109517 (14) The Laboratory of Virology and Infectious Disease, The Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125 (15) Department of Medicine, Weill Cornell Medicine, New York, NY, USA. ROR: https://ror.org/02r109517 Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. ROR: https://ror.org/02r109517 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine , New York, NY, USA. ROR: https://ror.org/02r109517 (16) Department of Medicine, Weill Cornell Medicine, New York, NY, USA. ROR: https://ror.org/02r109517 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine , New York, NY, USA. ROR: https://ror.org/02r109517 (17) Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ROR: https://ror.org/02yrq0923 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center , New York, NY, USA. Department of Dermatology, Weill Cornell Medical College, New York, NY, USA. ROR: https://ror.org/02r109517
