TY - JOUR
T1 - Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras–mutant lung cancer
AU - Yuan, Bo
AU - Clowers, Michael J.
AU - Velasco, Walter V.
AU - Peng, Stephen
AU - Peng, Qian
AU - Shi, Yewen
AU - Ramos-Castaneda, Marco
AU - Zarghooni, Melody
AU - Yang, Shuanying
AU - Babcock, Rachel L.
AU - Chang, Seon Hee
AU - Heymach, John V.
AU - Zhang, Jianjun
AU - Ostrin, Edwin J.
AU - Watowich, Stephanie S.
AU - Kadara, Humam
AU - Moghaddam, Seyed Javad
N1 - Publisher Copyright:
Copyright: © 2022, Yuan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2022/6/8
Y1 - 2022/6/8
N2 - K-ras–mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1β, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1β in the lungs of mice with K-rasG12D–mutant tumors (CC-LR mice). Here, we blocked IL-1β using an anti–IL-1β mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1β blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 [PD-1] expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1β blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.
AB - K-ras–mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1β, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1β in the lungs of mice with K-rasG12D–mutant tumors (CC-LR mice). Here, we blocked IL-1β using an anti–IL-1β mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1β blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 [PD-1] expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1β blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.
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U2 - 10.1172/jci.insight.157788
DO - 10.1172/jci.insight.157788
M3 - Article
C2 - 35471938
AN - SCOPUS:85131770711
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 11
M1 - e157788
ER -