Journal article
IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses
Proceedings of the National Academy of Sciences - PNAS, Vol.116(2), pp.599-608
01/08/2019
DOI: 10.1073/pnas.1814642116
PMCID: PMC6329954
PMID: 30587590
Abstract
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.
Details
- Title: Subtitle
- IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses
- Creators
- Rosa M Santana Carrero - Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77584Figen Beceren-Braun - Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77584Sarai C Rivas - The University of Texas MD Anderson Cancer CenterShweta M Hegde - The University of Texas MD Anderson Cancer CenterAchintyan Gangadharan - The University of Texas MD Anderson Cancer CenterDevin Plote - The University of Texas MD Anderson Cancer CenterGabriel Pham - The University of Texas MD Anderson Cancer CenterScott M Anthony - The University of Texas MD Anderson Cancer CenterKimberly S Schluns - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.116(2), pp.599-608
- DOI
- 10.1073/pnas.1814642116
- PMID
- 30587590
- PMCID
- PMC6329954
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- T32 CA009598 / NCI NIH HHS P30 CA016672 / NCI NIH HHS
- Language
- English
- Date published
- 01/08/2019
- Academic Unit
- Pathology
- Record Identifier
- 9984183982302771
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