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Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras-mutant lung cancer
Bo Yuan1,2, Michael J Clowers1,3, Walter V Velasco1
1Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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.
Insights
Blocking interleukin-1 beta (IL-1β) reduced lung tumor burden and promoted an antitumor immune response in K-ras-mutant lung adenocarcinoma. This suggests IL-1β blockade as a potential preventive and therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Inflammation
Background:
- K-ras-mutant lung adenocarcinoma (KM-LUAD) has a poor prognosis and is linked to tumor-promoting inflammation.
- Canakinumab, an IL-1β-targeting antibody, reduced lung cancer risk in a clinical trial.
- High IL-1β levels were observed in the lungs of mice with K-rasG12D-mutant tumors.
Purpose of the Study:
- To investigate the preventive and therapeutic effects of blocking IL-1β in a mouse model of KM-LUAD.
- To analyze the impact of IL-1β blockade on the tumor microenvironment and immune cell infiltration.
Main Methods:
- Administered an anti-IL-1β antibody to mice with K-rasG12D-mutant lung tumors at different ages (6 and 14 weeks).
- Assessed tumor burden, immune cell populations (CD8+ T cells, neutrophils, PMN-MDSCs), and cytokine expression.
- Correlated IL1B expression with immune cell infiltration and gene expression in human KM-LUAD patient data (TCGA).
Main Results:
- IL-1β blockade significantly reduced lung tumor burden in both preventive and therapeutic settings.
- Treatment led to an antitumor microenvironment with increased cytotoxic CD8+ T cells and decreased neutrophils and PMN-MDSCs.
- Human KM-LUAD data showed positive correlations between IL1B expression and immunosuppressive cell infiltration (PMNs, CXCL1) and PDCD1.
Conclusions:
- IL-1β blockade demonstrates potential as a preventive strategy for individuals at high risk of KM-LUAD.
- Targeting IL-1β may offer an alternative therapeutic approach for KM-LUAD, potentially in combination with existing treatments.
