Abstract 4051: Different immune signatures in advanced lung tumors of Nrf2 wildtype vs. knockout mice

Abstract

Abstract Activation of Nrf2 and its downstream target genes serves as a master defense mechanism, protecting cells against oxidative and electrophilic stress. Numerous activators of Nrf2 inhibit carcinogenesis. However, genetic alterations resulting in constitutive Nrf2 activation in human lung tumors promotes tumor growth and chemoresistance. The dual role of Nrf2 in cancer has generated a high level of interest, but little is known regarding the effect of Nrf2 on immune cells during lung carcinogenesis. In this study, we used the potent carcinogen vinyl carbamate to induce lung tumors in mice. Tumor burden, the immunophenotype, and genetic signatures were compared in the lungs of Nrf2 knockout (-/-, KO) vs. wildtype (+/+, WT) mice. Nrf2 KO mice were more susceptible to vinyl carbamate; these mice developed tumors earlier than the WT mice and exhibited more and larger tumors over times ranging from 20-32 weeks after initiation. By 32 weeks, WT mice have an average of 6.5 ± 0.95 tumors per lung compared to 12.25 ± 2.6 tumors in the KO mice. Immune cell populations including T cells (CD4+ and CD8+), B cells, macrophages and myeloid derived suppressor cells were investigated in the lungs and spleens of Nrf2 WT and KO mice challenged with vinyl carbamate. T cell populations were significantly (P < 0.05) reduced in the lungs of Nrf2 KO mice, while tumor-promoting macrophages and myeloid derived suppressor cells were elevated in the lung and spleen, respectively, of Nrf2 KO mice compared to WT mice. Moreover, immune response genes, especially a series of cytokines (Cxcl1, Cxcl12, Csf1, and Ccl9) and MHC antigens that promote tumor growth, were significantly upregulated in tumors from Nrf2-/- mice. Importantly, this expression profile is conserved in patients with lung cancer. Overall, our results confirmed a tumor protective role of Nrf2 in carcinogenesis and suggest an important regulatory role for Nrf2 in immune cells in both mouse and human lung tumors. Citation Format: Di Zhang, Jonathan Rennhack, Eran Andrechek, Cheryl Rockwell, Karen Liby. Different immune signatures in advanced lung tumors of Nrf2 wildtype vs. knockout mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4051.