IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses

Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):599-608. doi: 10.1073/pnas.1814642116. Epub 2018 Dec 26.


Previous studies have provided evidence that IL-15 expression within human tumors is crucial for optimal antitumor responses; however, the regulation of IL-15 within the tumor microenvironment (TME) is unclear. We report herein, in analyses of mice implanted with various tumor cell lines, soluble IL-15/IL-15Rα complexes (sIL-15 complexes) are abundant in the interstitial fluid of tumors with expression preceding the infiltration of tumor-infiltrating lymphocytes. Moreover, IL-15 as well as type I IFN, which regulates IL-15, was required for establishing normal numbers of CD8 T cells and natural killer cells in tumors. Depending on tumor type, both the tumor and the stroma are sources of sIL-15 complexes. In analyses of IL-15 reporter mice, most myeloid cells in the TME express IL-15 with CD11b+Ly6Chi cells being the most abundant, indicating there is a large source of IL-15 protein in tumors that lies sequestered within the tumor stroma. Despite the abundance of IL-15-expressing cells, the relative levels of sIL-15 complexes are low in advanced tumors but can be up-regulated by local stimulator of IFN genes (STING) activation. Furthermore, while treatment of tumors with STING agonists leads to tumor regression, optimal STING-mediated immunity and regression of distant secondary tumors required IL-15 expression. Overall, our study reveals the dynamic regulation of IL-15 in the TME and its importance in antitumor immunity. These findings provide insight into an unappreciated attribute of the tumor landscape that contributes to antitumor immunity, which can be manipulated therapeutically to enhance antitumor responses.

Keywords: CD8 T cells; interferons; interleukin 15; myeloid cells; tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / immunology*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-15 / genetics
  • Interleukin-15 / immunology*
  • Melanoma / genetics
  • Melanoma / immunology*
  • Melanoma / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Receptors, Interleukin-15 / genetics
  • Receptors, Interleukin-15 / immunology
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*


  • Il15ra protein, mouse
  • Interleukin-15
  • Membrane Proteins
  • Neoplasm Proteins
  • Receptors, Interleukin-15
  • Sting1 protein, mouse