Abstract
Because of insufficient migration and antitumor function of transferred T cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive cell transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T cells in vitro with a second T-cell receptor (TCR) that recognizes a bacterial antigen. We then transferred these dual-specific T cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T cells with an increased number and killing ability to the tumors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 740-745 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 114 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jan 24 2017 |
Funding
W.C. is supported by NIH Grant AI125741, the Blood-Center Research Foundation, the Wisconsin Breast Cancer Showhouse, an Ann's Hope Melanoma Research Award, and the Women's Health Research Program. G.X. is supported by The Elizabeth Elser Doolittle Postdoctoral Fellowship. D.M.S. is a member of the Medical Scientist Training Program at Medical College of Wisconsin, which is partially supported by a training grant from National Institute of General Medical Sciences T32-GM080202 and Grant F30DK108557 from National Institute of Diabetes and Digestive and Kidney Diseases.
Keywords
- Adoptive cell transfer
- CD8 T cells
- Immunotherapy
- Listeria
- Melanoma
ASJC Scopus subject areas
- General
