Abstract
Viral vectors are being used for the treatment of cancer. Yet, their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple tumor models that injection of tumor-bearing mice with this vector results in improved tumor control and survival. Importantly, r3LCMV improved tumor control in immunodeficient Rag1-/- mice and MyD88-/- mice, suggesting that multiple pathways contributed to the antitumoral effects. The antitumoral effects of r3LCMV were also observed when this vector was administered several weeks before tumor challenges, suggesting the induction of trained immunity. Single-cell RNA sequencing analyses, antibody blockade experiments, and knockout models revealed a critical role for host-intrinsic IFN-I in the antitumoral efficacy of r3LCMV vectors. Collectively, these data demonstrate potent antitumoral effects by r3LCMV vectors and unveil multiple mechanisms underlying their antitumoral efficacy.
| Original language | English (US) |
|---|---|
| Article number | e178945 |
| Journal | Journal of Clinical Investigation |
| Volume | 134 |
| Issue number | 15 |
| DOIs | |
| State | Published - 2024 |
Funding
We thank Juan Carlos De La Torre (Scripps Research Institute, La Jolla, California, USA) and Stephen Waggoner and Carolyn Rydyznski (Cincinnati Children's Medical Center, Cincinnati, Ohio, USA) for technical assistance in making the r3LCMV vectors. We thank Jennifer Wu, Bin Zhang, and Chyung-Ru Wang for discussions. We also thank Hookipa Biotech for sharing rLCMV vectors and for helpful discussions. We thank Rebecca Obeng for guidance on the tissue sectioning and immunostaining of tumor samples. We thank Ching Man Wai at the NUSeq core for help with the scRNA-Seq experiments. Several images were created with BioRender (biorender.com). This work was possible with a grant from the National Institute on Drug Abuse (DP2DA051912) to PPM, an Institutional Research Grant (IRG-15-173-21) from the American Cancer Society to PPM, and a pilot grant from the Lurie Cancer Center at Northwestern University. Flow cytometry samples were acquired at the Lurie Flow Cytometry Facility at Northwestern University. YRC and BA performed most of the mouse tumor challenge and immunogenicity experiments. Authorship order was decided mutually by these two co\u2013first authors. TD and NI helped to perform some of the mouse experiments. SF analyzed the gene expression data. PPM designed the experiments and secured funding. PPM wrote the paper with feedback from all authors. The gene expression analysis in this research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, the Feinberg\u2019s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. We thank Juan Carlos De La Torre (Scripps Research Institute, La Jolla, California, USA) and Stephen Waggoner and Carolyn Rydyznski (Cincinnati Children\u2019s Medical Center, Cincinnati, Ohio, USA) for technical assistance in making the r3LCMV vectors. We thank Jennifer Wu, Bin Zhang, and Chyung-Ru Wang for discussions. We also thank Hookipa Biotech for sharing rLCMV vectors and for helpful discussions. We thank Rebecca Obeng for guidance on the tissue sectioning and immunostaining of tumor samples. We thank Ching Man Wai at the NUSeq core for help with the scRNA-Seq experiments. Several images were created with BioRender (biorender.com). This work was possible with a grant from the National Institute on Drug Abuse (DP2DA051912) to PPM, an Institutional Research Grant (IRG-15-173-21) from the American Cancer Society to PPM, and a pilot grant from the Lurie Cancer Center at Northwestern University. Flow cytometry samples were acquired at the Lurie Flow Cytometry Facility at North-western University.
ASJC Scopus subject areas
- General Medicine
