TY - JOUR
T1 - IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses
AU - Santana Carrero, Rosa M.
AU - Beceren-Braun, Figen
AU - Rivas, Sarai C.
AU - Hegde, Shweta M.
AU - Gangadharan, Achintyan
AU - Plote, Devin
AU - Pham, Gabriel
AU - Anthony, Scott M.
AU - Schluns, Kimberly S.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Willem Overwijk for sharing IFNAR1−/− mice and tumor cell lines; Dr. Eric Pamer for the CCR2-DTR Tg mice; and Drs. Lynn Puddington, Ross Kedl, and Tomasz Zal for IL-15 transcriptional reporter mice, IL-15 translational reporter mice, and CCR2-RFP reporter mice, respectively. This research was supported by NIH Predoctoral Training Grant CA009598 (to S.M.A.), a seed fund from the Center for Inflammation and Cancer at the MD Anderson Cancer Center (to K.S.S.), and First year medical student summer research program, MD Anderson Cancer Center (to G.P.) Cancer Prevention Research Institute of Texas (K.S.S.).
Funding Information:
. We thank Dr. Willem Overwijk for sharing IFNAR1−/− mice and tumor cell lines; Dr. Eric Pamer for the CCR2-DTR Tg mice; and Drs. Lynn Puddington, Ross Kedl, and Tomasz Zal for IL-15 transcriptional reporter mice, IL-15 translational reporter mice, and CCR2-RFP reporter mice, respectively. This research was supported by NIH Predoctoral Training Grant CA009598 (to S.M.A.), a seed fund from the Center for Inflammation and Cancer at the MD Anderson Cancer Center (to K.S.S.), and First year medical student summer research program, MD Anderson Cancer Center (to G.P.) Cancer Prevention Research Institute of Texas (K.S.S.).
Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.
PY - 2019/1/8
Y1 - 2019/1/8
N2 - 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 + Ly6C hi 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.
AB - 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 + Ly6C hi 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.
KW - CD8 T cells
KW - Interferons
KW - Interleukin 15
KW - Myeloid cells
KW - Tumors
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U2 - 10.1073/pnas.1814642116
DO - 10.1073/pnas.1814642116
M3 - Article
C2 - 30587590
AN - SCOPUS:85059614253
SN - 0027-8424
VL - 116
SP - 599
EP - 608
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 2
ER -