Abstract 4636: p53 governs the tumoricidal activity of M1 macrophages in lung cancer

Abstract

Abstract Macrophages in a tumor microenvironment have been characterized as M1- and M2-polarized subtypes. M1 macrophage is associated with favorable clinical outcome of lung cancer patients, but the detail molecular mechanism is not thoroughly understood. Herein, we elucidate the anti-tumor mechanism of M1 macrophages by in vitro and in vivo assays. M1 conditioned media (CM) significantly reduced the tumor size in the xenograft mouse model via intratumoral administration. The M1-altered differential expression was profiled by microarray and the pathway analysis indicated that p53 was a critical regulator. Lung cancer cells harboring wild-type p53 (wt-p53) went apoptosis after M1 CM culture, but cells with mutant p53 did not. Additionally, M1 CM enhanced wt-p53 accumulation through reducing p53 ubiquitination and increasing protein stability. Moreover, we identified a p53 interacting protein STAT1 involved in M1-induced apoptosis and p53 accumulation. The M1 CM not only enhanced the interaction between STAT1 and p53 but also up-regulated and activated STAT1. We found that STAT1-Y701 phosphorylation is required for the p53 stability. The interaction of STAT1-Y701F and p53 was reduced compared to wild-type STAT1. To reveal the upstream signaling, we found that knockdown of IFNAR2, JAK1 and TYK2 attenuates M1-induced apoptosis. Taken together, STAT1 signaling is essential for M1 CM-induced apoptosis and p53 accumulation. Our findings imply that p53 and M1 macrophages play important roles in the immune surveillance in lung cancers. Citation Format: Yi-Jing Hsiao, Hsuan-Yu Chen, Kang-Yi Su, Bing-Ching Ho, Jeremy J.W. Chen, Pan-Chyr Yang, Sung-Liang Yu. p53 governs the tumoricidal activity of M1 macrophages in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4636. doi:10.1158/1538-7445.AM2017-4636