Abstract B72: Lineage specifiers SOX2 and NKX2-1 inversely regulate tumor cell fate and neutrophil recruitment in lung cancer

The major types of non-small cell lung cancer, squamous cell carcinoma and adenocarcinoma, have distinct tumor immune microenvironments. Understanding the mechanisms underlying these differences is of particular importance given the success and current limitations of immunotherapy. We developed multiple mouse models of lung cancer to demonstrate that NKX2-1 potently suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Furthermore, SOX2 recruits, whereas NKX2-1 suppresses, tumor-associated neutrophils (TANs) at least partly through inverse regulation of the chemoattractant CXCL5/6. Single-cell RNA sequencing revealed that TANs exhibit tumor-promoting features and distinct gene expression profiles compared to blood neutrophils. Finally, TANs cooperate with squamous-associated genetic alterations to promote squamous tumors. These data reveal how transcription factors with key functions in normal development dictate not only cancer cell identity but also distinct tumor immune microenvironments. Citation Format: Gurkan Mollaoglu, Alex Jones, Sarah Wait, Anandaroop Mukhopadhyay, Sangmin Jeong, Rahul Arya, Soledad Camolotto, Timothy Mosbruger, Chris Stubben, Christopher Conley, Arjun Bhutkar, Jeffery Vahrenkamp, Kristofer Berrett, Melissa Cessna, Thomas Lane, Benjamin Witt, Mohamed Salama, Jason Gertz, Kevin Jones, Eric Snyder, Trudy Oliver. Lineage specifiers SOX2 and NKX2-1 inversely regulate tumor cell fate and neutrophil recruitment in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B72.