Role of IKK alpha in lung cancer development

Division Of Basic Sciences - Nci

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Abstract

Previously, we reported that kinase-died Ikka knock-in (KA/KA) mice develop spontaneous lung squamous cell carcinomas (LSCCs), which require macrophages for tumor formation (Xiao et al., Cancer Cell 2013). Depleting macrophages prevents LSCC development. However, many CD4 T cells remain in the lungs of KA/KA mice. Thus, we hypothesize that although the CD4 T cells do not directly promote the lung tumorigenesis, their increased presence may program macrophages into a pro-tumor phenotype. Notably, lung CD4 T cells in KA/KA mice highly express Il4. To investigate the essential role of CD4 T cell-derived IL-4 and the IL-4-mediated pathway in lung tumorigenesis, we isolated CD4 T cells from KA/KA, KA/KA;Il4-/-, KA/KA;Il4r-/-, and KA/KA;Stat6-/- mice and injected them into KA/KA;Rag-/- mice that lack CD4 T cells and B cells. Only CD4 T cells from KA/KA mice induced LSCC, whereas CD4 T cells from KA/KA;Il4-/-, KA/KA;Il4r-/-, and KA/KA;Stat6-/- mice failed to do so. These results demonstrate that the IL-4/IL-4R/STAT6 signaling in CD4 T cells is required for LSCC development by sustaining high Il4 expression in pulmonary CD4 T cells. Importantly, we also found that IL-4-positive CD4 T cells express high levels of PD-1. However, anti-PD-1 antibody treatment did not prevent LSCC formation. This finding may help explain why some cancer patients do not respond well for anti-PD-1 therapy. Understanding the underlying mechanisms could inform the development of more effective clinical treatment strategies for cancer patients.