Targeting IL-1β as an Immunopreventive and Therapeutic Modality for K-Ras-Mutant Lung Cancer

Authors

Bo Yuan
Michael J Clowers
Walter V Velasco
Stephen Peng
Qian Peng
Yewen Shi
Marco Ramos-Castaneda
Melody Zarghooni
Shuanying Yang
Rachel L Babcock
Seon Hee Chang
John V Heymach
Jianjun Zhang
Edwin J Ostrin
Stephanie S Watowich
Humam Kadara
Seyed Javad Moghaddam

Publication Date

6-8-2022

Journal

JCI Insight

Abstract

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.

Keywords

Adenocarcinoma of Lung, Animals, Antibodies, Monoclonal, Humanized, Cytokines, Genes, ras, Humans, Interleukin-1beta, Lung Neoplasms, Mice, Molecular Targeted Therapy, Mutation, Neutrophils, Proto-Oncogene Proteins p21(ras), Tumor Microenvironment, Lung cancer, NF-kappaB, Neutrophils, Oncology

DOI

10.1172/jci.insight.157788

PMID

35471938

PMCID

PMC9220853

PubMedCentral® Posted Date

6-8-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes