Molecular Networks in Tumour Infiltrating T Cells

Friday, November 22, 2019 -
2:00pm to 3:00pm
The FUNG Auditorium
Anjana Rao
La Jolla Institute for Immunology
Adjunct Professor of Pharmacology
Department of Pharmacology and Moores Cancer Center, University of California at San Diego
Sanford Consortium for Regenerative Medicine, La Jolla, California, USA

 

Molecular Networks in Tumour Infiltrating T Cells

Abstract: 

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.

Bio: 

Dr. Anjana Rao obtained her Ph.D. in Biophysics from Harvard University and was a Professor at Harvard Medical School until 2011, when she moved to the La Jolla Institute and UCSD (University of California in San Diego). Her research is focused on the regulation of gene expression, using immune cells, haematopoietic stem cells and embryonic stem cells as model systems. Her lab purified and molecularly characterized the calcium/ calcineurin-regulated transcription factor NFAT; defined diverse transcriptional programs regulated by NFAT proteins in T cells; identified the pore subunit of the store-operated Ca2+ channel, ORAI1; and discovered that proteins of the TET family are enzymes that mediate DNA demethylation and regulate gene expression by oxidizing 5-methylcytosine. In recent studies, her lab has defined the role of NFAT and other transcription factors in anti-tumor responses, and explored the roles of TET proteins and oxidized methylcytosines in the immune/ haematopoietic systems and in embryonic development and oncogenesis. Dr. Rao has received numerous awards throughout her career. She is an elected member/fellow of the US National Academy of Sciences, the American Academy of Arts and Sciences and the American Association for the Advancement of Science, and has received an Outstanding Investigator Award from the National Cancer Institute, National Institutes of Health, USA. She has mentored more than 100 students and post-doctoral fellows, a number of whom have gone on to leadership positions in science-related fields.