PRMT1 acts as a suppressor of MHC-I and anti-tumor immunity
Tirta M. Djajawi,
Lizzy Pijpers,
Akash Srivaths,
David Chisanga,
Kok Fei Chan,
Simon J. Hogg,
Liam Neil,
Sarahi Mendoza Rivera,
Nenad Bartonicek,
Sarah L. Ellis,
Terry C.C. Lim Kam Sian,
Pouya Faridi,
Yang Liao,
Bhupinder Pal,
Andreas Behren,
Wei Shi,
Stephin J. Vervoort,
Ricky W. Johnstone,
Conor J. Kearney
Affiliations
Tirta M. Djajawi
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
Lizzy Pijpers
Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
Akash Srivaths
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
David Chisanga
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
Kok Fei Chan
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
Simon J. Hogg
Oncology Discovery, AbbVie, South San Francisco, CA 94080, USA
Liam Neil
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
Sarahi Mendoza Rivera
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Nenad Bartonicek
Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
Sarah L. Ellis
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
Terry C.C. Lim Kam Sian
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; Monash Proteomics and Metabolomics Platform, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC 3800, Australia; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC 3168, Australia
Pouya Faridi
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; Monash Proteomics and Metabolomics Platform, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC 3800, Australia; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC 3168, Australia
Yang Liao
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
Bhupinder Pal
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
Andreas Behren
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
Wei Shi
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
Stephin J. Vervoort
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
Ricky W. Johnstone
Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
Conor J. Kearney
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia; Corresponding author
Summary: Cancer immunotherapies have demonstrated remarkable success; however, the majority of patients do not respond or develop resistance. Here, we conduct epigenetic gene-targeted CRISPR-Cas9 screens to identify epigenomic factors that limit CD8+ T cell-mediated anti-tumor immunity. We identify that PRMT1 suppresses interferon gamma (Ifnγ)-induced MHC-I expression, thus dampening CD8+ T cell-mediated killing. Indeed, PRMT1 knockout or pharmacological targeting of type I PRMT with the clinical inhibitor GSK3368715 enhances Ifnγ-induced MHC-I expression through elevated STAT1 expression and activation, while re-introduction of PRMT1 in PRMT1-deficient cells reverses this effect. Importantly, loss of PRMT1 enhances the efficacy of anti-PD-1 immunotherapy, and The Cancer Genome Atlas analysis reveals that PRMT1 expression in human melanoma is inversely correlated with expression of human leukocyte antigen molecules, infiltration of CD8+ T cells, and overall survival. Taken together, we identify PRMT1 as a negative regulator of anti-tumor immunity, unveiling clinical type I PRMT inhibitors as immunotherapeutic agents or as adjuncts to existing immunotherapies.
