Abstract IA13: The interplay between tumor cells, cancer associated fibroblasts, and immature myeloid cells in the esophageal tumor microenvironment
Authors: Karakasheva Tatiana , Lin Eric , Hicks Phil , Waldron Todd , Rustgi Anil K. 
Published: October 2016

Abstract
Esophageal cancer has two major subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC is more common worldwide and illustrative of other SCCs (e.g. head/neck, lung) from a molecular pathogenesis viewpoint. EAC is rising in incidence in the United States and Western Europe. Unfortunately, 5-year survival remains dismal for both types, at about 15%. Interrogation of the esophageal tumor microenvironment, replete with desmoplasia, CAFs and diverse immune cells, may afford opportunities to reveal new therapeutic targets, especially in a combinatorial fashion.
We have generated previously a conditional knockout model of p120-catenin whereby mice develop preneoplastic and neoplastic lesions in the esophagus. Tumor-derived cells secrete granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNFα). The tumors contain significant desmoplasia and immune cell infiltration. Immature myeloid cells (myeloid deriver suppressor cells or MDSCs) comprise a significant percentage of the immune cells present and likely participate in fostering a favorable tumor microenvironment, including the activation of fibroblasts. We have identified CD38 as playing a vital role in MDSC biology. CD38 belongs to the ADP-ribosyl cyclase family and possesses both ectoenzyme and receptor functions. It has been described to function in lymphoid and early myeloid cell differentiation, cell activation, and neutrophil chemotaxis. CD38high MDSCs are more immature than MDSCs lacking CD38 expression, suggesting a potential role for CD38 in the maturation halt found in MDSC populations. CD38high MDSCs also possess a greater capacity to suppress activated T cells, and promote tumor growth to a greater degree than CD38low MDSCs, likely as a result of increased iNOS production. In addition, we have identified novel tumor–derived factors, specifically IL-6, IGFBP3, and CXCL16, which induce CD38 expression by MDSCs ex vivo. Finally, we have detected an expansion of CD38+ MDSCs in peripheral blood of advanced-stage cancer patients. Additional work reveals cross-talk between CAFs and tumor cells through the induction of IL-6 and RANTES, suggesting there is interaction between tumor cells, CAFs and MDSCs. In aggregate, we find that CD38 (on MDSCs), IL-6 and RANTES (secreted by tumor cells and CAFs) serve to provide novel approaches in therapy.
Citation Format: Tatiana Karakasheva, Eric Lin, Phil Hicks, Todd Waldron, Anil K. Rustgi. The interplay between tumor cells, cancer associated fibroblasts, and immature myeloid cells in the esophageal tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA13.