The Immunomodulatory Effects of Nrf2 Activation on Macrophages in the Lung Tumor Microenvironment

Project Summary There is a critical need for the development of new therapies for lung cancer, as current treatments are ineffective and the five-year survival rate remains below 20%. The immune infiltrate in the lung tumor microenvironment is a promising target for anti-cancer therapy. Macrophages make up the majority of this immune population and

exist on a dynamic spectrum which can either be anti-cancer or cancer-promoting. In developed tumors, a pro- inflammatory phenotype in macrophages is beneficial for an anti-tumor immune response. To survive in this inflammatory environment, macrophages rely on cytoprotective mechanisms regulated by the Nrf2 pathway. This

pathway serves as a defense mechanism against oxidative stress and protects normal, healthy cells from malignant transformation. While constitutive Nrf2 activation in tumor cells can aid tumor cell survival, the effect that Nrf2 activation has on immune cells in the tumor microenvironment is surprisingly underexplored. Synthetic

derivatives of oleanane triterpenoids are the most potent known pharmacological activators of the Nrf2 pathway, and the triterpenoid CDDO-Methyl ester (CDDO-Me) has potent anti-tumor activity in a preclinical mouse model of lung cancer. Tumor-educated bone marrow-derived macrophages (BMDMs) increase pro-inflammatory

markers associated with an anti-tumor immune response and decrease pro-tumor chemotactic and angiogenic factors when treated with CDDO-Me. Therefore, I hypothesize that by inducing an anti-tumor macrophage phenotype within the tumor microenvironment, Nrf2 activation will decrease lung tumor burden. Aim 1 of this

proposal will determine if Nrf2 activation in macrophages increases their anti-tumor function. Aim 2 will evaluate whether Nrf2 activation in tumor cells polarizes tumor-associated macrophages to promote tumor growth and if pharmacological Nrf2 activation in the microenvironment can overcome the effect of Nrf2 activation in mutated

tumor cells to reduce tumor burden. This proposal includes a comprehensive training plan including didactic and experimental learning in both in vitro and in vivo model systems, transcriptomics, genome editing, and novel in vivo imaging techniques. Completion of the proposed studies will provide me with the necessary skills and

rigorous training needed for success as an independent and collaborative investigator in cancer biology.