Thursday, November 21, 2024
11/21/2024
Despite the reduction in incidence rates for lung cancer in the United States as tobacco use has declined, lung cancer remains the leading cause of cancer deaths. The introduction of new targeted therapies and immunotherapy has been beneficial for patients with certain genetic mutations, but the 5-year survival rates for lung cancer remain unacceptably low. Former smokers retain an elevated risk of developing lung cancer, and these patients would benefit from early intervention with a safe, effective drug. Dietary components that activate the Nrf2/Keap1 cytoprotective pathway inhibit the development of lung and other cancers in preclinical models and reduce cancer risk in humans. Genetic inactivation of Nrf2 increases susceptibility to developing cancer from environmental challenges. However, mutations in either Nrf2 or Keap1 have been identified in lung and other cancers, leading to constitutive activation of the pathway, tumor survival and resistance to chemotherapy. Unexpectedly, we recently identified a novel immune signature in the lungs and tumors of Nrf2 knockout (KO) mice compared to wildtype (WT) mice. Changes in immune cells (higher numbers of tumor-promoting macrophages and myeloid-derived suppressor cells (MDSCs) and decreased cytotoxic T cells) and expression of more than 30 immune response genes, including a series of cytokines relevant in human lung cancer, were identified in lung tumors from the Nrf2 KO mice. The Nrf2 KO mice also had a higher lung tumor burden than the WT mice. These results confirmed a protective role for Nrf2, even in late-stage carcinogenesis, and suggest that activation of Nrf2 in immune cells may be advantageous for preventing or treating lung cancer. These studies are clinically relevant, as the triterpenoid CDDO-methyl ester (CDDO-Me) is being tested in phase 3 trials for several chronic diseases. This potent Nrf2 activator reduced the number, size, and pathology of lung tumors when used for prevention or treatment of lung cancer. CDDO-Me is a potent anti-inflammatory agent, and mechanisms for suppressing inflammation and carcinogenesis can be Nrf2-dependent or independent. We hypothesize that Nrf2-dependent modulation of macrophages, MDSCs and T cells can suppress lung carcinogenesis. In addition, we hypothesize that pharmacological activation of Nrf2 with CDDO-Me will inhibit infiltration of tumor-promoting immune cells and reduce secretion of pro-tumorigenic cytokines to prevent or treat lung cancer. We will use Nrf2 WT and KO mice and pharmacological Nrf2 activators and inhibitors to a) define changes in immune cell populations as lung tumors progress, b) test the effects of pharmacological activators and inhibitors of Nrf2 to modulate immune cell activity in vitro and in vivo, and c) compare the efficacy of Nrf2 activators or inhibitors for prevention and treatment of experimental lung cancer. We will also extend our results to human NSCLC by characterizing activation of the Nf2 pathway in both immune cells and tumor cells in archived human lung cancer samples at various stages and grades.
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