Tumorigenesis is accompanied by broad changes to the surrounding tissue microenvironment in a tumor- and patient-specific manner. Phenotype shifts in tissue-resident immune cells promote cancer progression by establishing a proliferative inflammatory environment, activating angiogenesis, stimulating tumor cell invasion and suppressing anti-tumor immunity. While the former mechanisms are well appreciated and often targeted by current cancer therapeutics, the nature of the mechanisms controlling establishment of the local immunosuppressive state that contribute to a failure of anti-tumor immunity are less clearly defined. Blockade of tumor antigen-specific T cell killing is clearly a major contributor to the failure to control tumorigenesis. However, evidence suggests that phenotypic shifts in innate immune cell populations also contribute to the failure of anti-tumor immunity. We hypothesize that the emergence of early lung adenocarcinomas is accompanied by a shift in myeloid phenotypes, rapidly establishing a microenvironment favorable to tumor growth, survival and vascularization, and hostile to cell-mediated anti-tumor immune responses. Through the utilization of a Cre-inducible mouse model of p53-null, Kras-G12D+ lung adenocarcinoma, we have begun to define the natural history of the myeloid component of the tumor microenvironment, from tumor initiation to a point equivalent to human stage I adenocarcinoma. Histological, flow cytometry and real-time PCR approaches collectively demonstrate that tumor-associated myeloid phenotypes emerge at a very early stage of disease. These data are consistent with our hypothesis that the myeloid component of the tumor microenvironment plays a crucial role in establishing an immunosuppressive state during early tumorigenesis. Implications of these findings for current and emerging immunotherapies will be discussed.
Citation Format: Mouna Lagraoui, Clifton L. Dalgard, Gauthaman Sukumar, Celeste Huaman, Thomas Summers, Corey A. Carter, Brian C. Schaefer. Establishing the natural history of the immunosuppressive myeloid microenvironment in an inducible model of lung adenocarcinoma [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 4000. doi:10.1158/1538-7445.AM2017-4000