Ong, CEB and Patchett, AL and Darby, JM and Chen, J and Liu, G and Lyons, AB and Woods, GM and Flies, AS, NLRC5 regulates expression of MHC-I and provides a target for anti-tumor immunity in 3 transmissible cancers, Journal of Cancer Research and Clinical Oncology, 147, (7) pp. 1973-1991. ISSN 0171-5216 (2021) [Refereed Article]
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Purpose:Downregulation of MHC class I (MHC-I) is a common immune evasion strategy of many cancers. Similarly, two allogeneic clonal transmissible cancers have killed thousands of wild Tasmanian devils (Sarcophilus harrisii) and also modulate MHC-I expression to evade anti-cancer and allograft responses. IFNG treatment restores MHC-I expression on devil facial tumor (DFT) cells but is insufficient to control tumor growth. Transcriptional co-activator NLRC5 is a master regulator of MHC-I in humans and mice but its role in transmissible cancers remains unknown. In this study, we explored the regulation and role of MHC-I in these unique genetically mis-matched tumors.
Methods: We used transcriptome and flow cytometric analyses to determine how MHC-I shapes allogeneic and anti-tumor responses. Cell lines that overexpress NLRC5 to drive antigen presentation, and B2M-knockout cell lines incapable of presenting antigen on MHC-I were used to probe the role of MHC-I in rare cases of tumor regressions.
Results: Transcriptomic results suggest that NLRC5 plays a major role in MHC-I regulation in devils. NLRC5 was shown to drive the expression of many components of the antigen presentation pathway but did not upregulate PDL1. Serum from devils with tumor regressions showed strong binding to IFNG-treated and NLRC5 cell lines; antibody binding to IFNG-treated and NRLC5 transgenic tumor cells was diminished or absent following B2M knockout.
Conclusion: MHC-I could be identified as a target for anti-tumor and allogeneic immunity. Consequently, NLRC5 could be a promising target for immunotherapy and vaccines to protect devils from transmissible cancers and inform development of transplant and cancer therapies for humans.
|Item Type:||Refereed Article|
|Keywords:||transmissible cancer, devil facial tumor, allograft, MHC-I, NLRC5, immune evasion, immune checkpoint|
|Research Division:||Biological Sciences|
|Research Field:||Animal immunology|
|Objective Division:||Expanding Knowledge|
|Objective Group:||Expanding knowledge|
|Objective Field:||Expanding knowledge in the biological sciences|
|UTAS Author:||Ong, CEB (Ms Chrissy Ong)|
|UTAS Author:||Patchett, AL (Dr Amanda Patchett)|
|UTAS Author:||Darby, JM (Ms Jocelyn Darby)|
|UTAS Author:||Chen, J (Ms Jane Chen)|
|UTAS Author:||Liu, G (Associate Professor Guei-Sheung Liu)|
|UTAS Author:||Lyons, AB (Associate Professor Bruce Lyons)|
|UTAS Author:||Woods, GM (Professor Gregory Woods)|
|UTAS Author:||Flies, AS (Dr Andy Flies)|
|Funding Support:||Australian Research Council (DE180100484)|
|Deposited By:||Menzies Institute for Medical Research|
|Downloads:||8 View Download Statistics|
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