T-cell activation promotes tumorigenesis in inflammation-associated cancer

Dan Rauch,Michael Lairmore,David Piwnica-Worms,Stefan Niewiesk,John Harding,Shimon Gross,Sirosh Bokhari,Lee Ratner

doi:10.1186/1742-4690-6-116

Abstract

Chronic inflammation has long been associated with a wide range of malignancies, is now widely accepted as a risk factor for development of cancer, and has been implicated as a promoter of a variety of cancers including hematopoietic malignancies. We have described a mouse model uniquely suited to examine the link between inflammation and lymphoma in which the Tax oncogene, expressed in activated T and NK cells, perpetuates chronic inflammation that begins as microscopic intraepithelial lesions and develops into inflammatory nodules, subcutaneous tumors, and large granular lymphocytic leukemia. The use of bioluminescent imaging in these mice has expanded our ability to interrogate aspects of inflammation and tumorigenesis non-invasively. Here we demonstrate that bioluminescence induction in these mice correlated with inflammation resulting from wounding, T cell activation, and exposure to chemical agents. In experiments in which long-term effects of inflammation on disease outcome were monitored, the development of lymphoma was promoted by an inflammatory stimulus. Finally we demonstrated that activation of T-cells in T-cell receptor (TCR) transgenic TAX-LUC animals dramatically exacerbated the development of subcutaneous TCR- CD16+ LGL tumors. The role of activated T-cells and acquired immunity in inflammation-associated cancers is broadly applicable to hematopoietic malignancies, and we propose these mice will be of use in dissecting mechanisms by which activated T-cells promote lymphomagenesis in vivo.

Highlights

Malignant transformation of the cancer cell is promoted and often preceded by changes in the tumor microenvironment, rich in inflammatory cells, growth factors, and DNA damage promoting agents
We have developed and characterized a triple transgenic mouse model of inflammation-associated cancer that allows us to experimentally activate T cells and NFkB signaling pathways prior to the onset of tumorigenesis and to non-invasively monitor inflammation and tumor progression using bioluminescent imaging (BLI)
We discovered that the activation of T- cells in triple transgenic mice dramatically exacerbated tumor development and the onset and dissemination of large granular lymphocytes (LGLs) lymphoma

Summary

Introduction

Malignant transformation of the cancer cell is promoted and often preceded by changes in the tumor microenvironment, rich in inflammatory cells, growth factors, and DNA damage promoting agents. A wide range of malignancies are promoted by chronic inflammation associated with chemical, physical, or microbial factors [1,2,3,4]. The diversity of oncogenic factors associated with inflammation highlights the importance of characterizing those common to a wide range of malignancies. T-cells are central regulators of the immune response; Tcells are recruited to sites of chronic inflammation, and the infiltration of T-cells within the tumor is a critical determinant of neoplastic outcome. More recently TH17 cells have been characterized for their ability to promote inflammation by recruiting neutrophils to peripheral tissues to remove extracellular pathogens, while Treg cells repress inflammation to keep immune hyperactivity in check. While there is no question that T-cells are recruited to sites of chronic inflammation, it is unclear whether activated T-cells promote or restrict malignancies in vivo

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Conclusion