Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras–mutant lung cancer
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
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
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Research Article Oncology

Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras–mutant lung cancer

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.

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

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Figure 3

Immunopreventive blockade of IL-1β modulates the TME to an antitumor immune phenotype.

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Immunopreventive blockade of IL-1β modulates the TME to an antitumor imm...
(A) Representative flow cytometry analysis of CD8+ T cells and percentage of CD8+ T cells in the whole lung (n = 5). (B) Representative flow cytometry analysis of CD3+ programmed cell death 1–positive (PD-1+) T cells and percentage of CD3+PD-1+ T cells in the whole lung (n = 3–4). (C) Representative flow cytometry analysis of regulatory Tregs and percentage of Tregs in the whole lung (n = 4–5). (D–F) Relative mRNA expression of (D) Cd8a, (E) Gzmb, and (F) Pdcd1 in the whole lung, normalized to Cd45 or Actb expression (n = 7–9). (G and H) MFI of (G) IFN-γ and (H) granzyme B measured by multiplex ELISA in IgG or anti–IL-1β Ab–treated mice (n = 7–8). (I) Representative photomicrographs and (J) quantification of IF staining with anti-CD8a (red) and DAPI (blue) in tumor lesions (left top and bottom: original magnification, ×20, scale bar: 50 μm; right top and bottom: ×40, scale bar: 20 μm.) n = 7–8. (K) Correlation between IL1B expression and infiltration of CD8+ T cells in LUAD (n = 535). (L) Correlation between IL1B expression and PDCD1 expression in LUAD (n = 535). (M) Correlation between IL1B expression and PDCD1 expression in KM-LUAD (n = 139). Data represent mean ± SEM. *P < 0.5 by unpaired t test. a IL-1β, anti–IL-1β; TPM, transcript count per million.