Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors

// Emily J. Colbeck 1,* , James P. Hindley 1,* , Kathryn Smart 1 , Emma Jones 1 , Anja Bloom 1 , Hayley Bridgeman 1 , Rhoanne C. McPherson 2 , Darryl G. Turner 2 , Kristin Ladell 1 , David A. Price 1 , Richard A. O’Connor 2 , Stephen M. Anderton 2 , Andrew J. Godkin 1 and Awen M. Gallimore 1 1 Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, UK 2 MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research and Centre for Immunity Infection and Evolution, University of Edinburgh, Edinburgh, UK * These authors have Contributed equally to this work Correspondence to: Awen M. Gallimore, email: // Keywords : Treg, cancer, proliferation, T-bet, CD69, Immunology Section,  Immunity, Immune response Received : July 18, 2015 Accepted : August 22, 2015 Published : September 10, 2015 Abstract Foxp3 + regulatory T cells (Tregs) are often highly enriched within the tumor-infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3 + T-bet + ‘T H 1-like’ Tregs which are thymus-derived Helios + cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent. Moreover, we show that the T H 1 phenotype of tumor-infiltrating Tregs is dispensable for their ability to influence tumor progression. We did however find that unlike Tconvs, the majority of intra-tumoral Tregs express the activation markers CD69, CD25, ICOS, CD103 and CTLA4 and are significantly more proliferative than Tconvs. Moreover, we have found that CD69 + Tregs are more suppressive than their CD69 - counterparts. Collectively, these data indicate superior activation of Tregs in the tumor microenvironment, promoting their suppressive ability and selective proliferation at this site.