TY - JOUR
T1 - Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity
AU - Li, Xuefeng
AU - Huntoon, Kristin
AU - Wang, Yifan
AU - Lee, Dae Yong
AU - Dong, Shiyan
AU - Antony, Abin
AU - Walkey, Carl
AU - Kim, Betty Y.S.
AU - Jiang, Wen
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2024/3/1
Y1 - 2024/3/1
N2 - Ionizing radiation is known to possess immune modulatory properties. However, how radiotherapy (RT) may complement with different types of immunotherapies to boost antitumor responses is unclear. In mice implanted with EO771 syngeneic tumors, NL-201 a stable, highly potent CD25-independent agonist to IL2 and IL15 receptors with enhanced affinity for IL2Rbg was given with or without RT. Flow analysis and Western blot analysis was performed to determine the mechanisms involved. STING (-/-) and CD11cþ knockout mice were implanted with EO771 tumors to confirm the essential signaling and cell types required to mediate the effects seen. Combination of RT and NL-201 to enhance systemic immunotherapy with an anti-PD-1 checkpoint inhibitor was utilized to determine tumor growth inhibition and survival, along characterization of tumor microenvironment as compared with all other treatment groups. Here, we showed that RT, synergizing with NL-201 produced enhanced antitumor immune responses in murine breast cancer models. When given together, RT and NL-201 enhanced activation of the cytosolic DNA sensor cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway, resulting in increased type I IFN production in dendritic cells (DC), and consequently greater tumor infiltration and more efficient priming of antigen-specific T cells. The immune stimulatory mechanisms triggered by NL-201 and RT resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic cancers. Our results support further preclinical and clinical investigation of this novel synergism regimen in locally advanced and metastatic settings.
AB - Ionizing radiation is known to possess immune modulatory properties. However, how radiotherapy (RT) may complement with different types of immunotherapies to boost antitumor responses is unclear. In mice implanted with EO771 syngeneic tumors, NL-201 a stable, highly potent CD25-independent agonist to IL2 and IL15 receptors with enhanced affinity for IL2Rbg was given with or without RT. Flow analysis and Western blot analysis was performed to determine the mechanisms involved. STING (-/-) and CD11cþ knockout mice were implanted with EO771 tumors to confirm the essential signaling and cell types required to mediate the effects seen. Combination of RT and NL-201 to enhance systemic immunotherapy with an anti-PD-1 checkpoint inhibitor was utilized to determine tumor growth inhibition and survival, along characterization of tumor microenvironment as compared with all other treatment groups. Here, we showed that RT, synergizing with NL-201 produced enhanced antitumor immune responses in murine breast cancer models. When given together, RT and NL-201 enhanced activation of the cytosolic DNA sensor cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway, resulting in increased type I IFN production in dendritic cells (DC), and consequently greater tumor infiltration and more efficient priming of antigen-specific T cells. The immune stimulatory mechanisms triggered by NL-201 and RT resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic cancers. Our results support further preclinical and clinical investigation of this novel synergism regimen in locally advanced and metastatic settings.
UR - http://www.scopus.com/inward/record.url?scp=85186961120&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85186961120&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-23-0236
DO - 10.1158/1535-7163.MCT-23-0236
M3 - Article
C2 - 37956421
AN - SCOPUS:85186961120
SN - 1535-7163
VL - 23
SP - 330
EP - 342
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 3
ER -