Abstract 2939: Tumor associated myeloid cell transcriptome signatures in an inducible Kras-positive lung adenocarcinoma murine model
Authors: Dalgard Clifton L. , Lagraoui Mouna , Sukumar Gauthaman , Huaman Celeste , Carter Corey A. , Schaefer Brian C. 
Published: July 2017

Tumorigenesis is modified by dynamic activities in the tumor microenvironment and mechanisms driving these alterations during tumor progression may be tumor- and patient-specific. Of well-established functions for tumor-associated stromal cells (e.g. angiogenesis, chemotaxis) immune system regulation by the tumor microenvironment is less well understood in their mechanism and effects. However, diminished activity of antigen-specific T cell lymphocytes tumor cytotoxicity is tumor promoting and recent cancer immunotherapy have targeted immune inhibitory checkpoints (e.g. anti-PD-L1) to restore T cell activity. Recent studies suggest that tumor-associated myeloid cells play a role in immunosuppression in several human cancers, including lung cancer. We hypothesize that early tumors of the lung promote changes in the phenotype of tumor-proximal myeloid cells, establishing an immunosuppressive microenvironment. As a component to observe this immunosuppressive role for myeloid cells, we performed specific transcriptome profiling of myeloid cells by immunomagnetic selection of CD11b-positive cells from lung tumors of a murine inducible Kras-positive, p53-negative cancer model. RNA sequencing of isolated myeloid cells as a function of tumorigenesis duration (3-18 weeks) establishes the kinetics of gene expression changes associated with tumor-supporting and immune-suppressing functions. Genome-wide expression analysis of myeloid cells between tumor-inducing adenovirus-Cre injected and normal control subjects resulted in identifying 1,883 genes with differential expression. Gene set enrichment analysis resulted in the stratification of samples by well-established gene signatures and tumor-promoting activity for angiogenesis (32 genes), lung tissue remodeling (47 genes) and cell survival (11 genes). Interestingly, a significant downregulated gene signature was observed in tumor-associated myeloid cells for immune cell chemotaxis (12 genes) and positive regulation of immune system activation (12 genes). These non-canonical gene signatures may identify a myeloid phenotype for immunosuppressive function with altered expression of genes such as L-selectin (Sell), C-C chemokine receptor type 7 (Ccr7), C-C motif chemokine (Ccl20) and CMRF35-like molecule 7 (CD300lb). The results shown are first steps in our tasks to define the phenotypes and mechanisms linking myeloid cells to tumor-associated immunosuppression in lung cancer.

Citation Format: Clifton L. Dalgard, Mouna Lagraoui, Gauthaman Sukumar, Celeste Huaman, Corey A. Carter, Brian C. Schaefer. Tumor associated myeloid cell transcriptome signatures in an inducible Kras-positive lung adenocarcinoma murine model [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 2939. doi:10.1158/1538-7445.AM2017-2939