Stellas and Karaliota et al. showed that locoregional monotherapy with heterodimeric IL-15/IL-15Rα (hetIL-15) exerted strong local and systemic antitumor activity, eradicated tumors in 40% of treated mice, reduced metastasis, and induced tumor-specific immunological memory against breast cancer cells in orthotopically implanted murine TNBC tumors. hetIL-15 promoted the intratumoral accumulation of cytotoxic lymphocytes, cDC1s, and a previously unrecognized distinct DC population (CD103intCD11b+ DCs) that has phenotypic and transcriptional similarities with monocyte-derived DCs and correlates with tumor regression.
Contributed by Shishir Pant
ABSTRACT: Locoregional monotherapy with heterodimeric interleukin (IL)-15 (hetIL-15) in a triple-negative breast cancer (TNBC) orthotopic mouse model resulted in tumor eradication in 40% of treated mice, reduction of metastasis, and induction of immunological memory against breast cancer cells. hetIL-15 re-shaped the tumor microenvironment by promoting the intratumoral accumulation of cytotoxic lymphocytes, conventional type 1 dendritic cells (cDC1s), and a dendritic cell (DC) population expressing both CD103 and CD11b markers. These CD103(int)CD11b(+)DCs share phenotypic and gene expression characteristics with both cDC1s and cDC2s, have transcriptomic profiles more similar to monocyte-derived DCs (moDCs), and correlate with tumor regression. Therefore, hetIL-15, a cytokine directly affecting lymphocytes and inducing cytotoxic cells, also has an indirect rapid and significant effect on the recruitment of myeloid cells, initiating a cascade for tumor elimination through innate and adoptive immune mechanisms. The intratumoral CD103(int)CD11b(+)DC population induced by hetIL-15 may be targeted for the development of additional cancer immunotherapy approaches.
Author Info: (1) Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Chemical Biology, National
Author Info: (1) Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece. Electronic address: george.pavlakis@nih.gov. (2) Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA. (3) Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Pharmacology, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece. (4) Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA. (5) Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA. (6) Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA. (7) Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA. (8) Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA. (9) Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA. Electronic address: george.pavlakis@nih.gov.
