Molecular Networks in Tumour Infiltrating T Cells

J Chen, H Seo, JP Scott-Browne, RM Pereira, GJ Martinez, S Trifari, GP Mognol, PG Hogan, A Rao

When exposed to chronic viral  infections or the tumour microenvironment, CD8⁺ T cells show a gradual decrease in effector function (often referred to as “exhaustion”), which results in hyporesponsiveness to further stimulation and impairs their immune response. We have used several models of bacterial and viral infection and anti-tumour responses to define a transcriptional network that mediates CD8⁺ T cell exhaustion. We demonstrate that the calcium- and calcineurin-regulated transcription factor NFAT controls the transcriptional programme of T cell exhaustion, especially in the absence of its transcriptional partner AP-1 (FOS-JUN). CD8⁺ T cells expressing an engineered form of NFAT1 unable to interact with AP-1 showed diminished T cell receptor (TCR) signaling, increased expression of inhibitory cell surface receptors, and diminished ability to protect against Listeria infection and to attenuate tumor growth in vivo. Genes directly induced by the engineered NFAT1 and its NR4A and TOX transcription factor targets overlapped with the genes expressed in exhausted CD8⁺ T cells in vivo. By extending our studies to a model in which tumour-infiltrating T cells express a chimeric antigen receptor (CAR), we demonstrate that NFAT imposes T cell exhaustion through induction of at least two families of secondary transcription factors, the NR4A nuclear receptor family and the high-mobility group (HMG)-box transcription factors TOX and TOX2. We provide evidence for positive regulation of NR4A by TOX and of TOX by NR4A, and suggest that interfering with NFAT, TOX and/or NR4A expression or activity has promise for cancer immunotherapy.