Oral Presentation CD1-MR1 2024

Characterising MAIT cell function in vivo in models of glioblastoma (#80)

Eleanor M Eddy 1 , Davide Moi 2 , Timothy P Patton 1 , Adam G Nelson 1 , Phoebe M Dewar 1 , Jeremy P Le 1 , Hamish EG McWilliam 1 , Jieru Deng 1 , Huimeng Wang 1 3 , Roberta Mazzieri 2 , Riccardo Dolcetti 2 , Jeffrey YM Mak 4 , David P Fairlie 4 , James McCluskey 1 , Zhenjun Chen 1 , Alexander D Barrow 1 , Alexandra J Corbett 1
  1. University of Melbourne, Melbourne, VIC, Australia
  2. Centre for Cancer Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, Guangzhou, China
  4. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

Mucosal-associated invariant T (MAIT) cells have a well-defined protective role in bacterial infection, due to their rapid activation in response to small metabolite antigens derived from the riboflavin synthesis pathway, presented on MHC related protein MR1 (Reantragoon et. al., 2012). As well as their capacity for anti-microbial cytotoxicity and cytokine production (Rudak et. al. 2018), emerging functions have also been described for MAIT cells in homeostasis, tissue repair, cancer and autoimmunity (eg. Leng at. al. 2019).

A tissue-resident population of MAIT cells was recently identified in the brain and found to perform important homeostatic functions (Zhang et. al. 2022). Additionally, there is evidence indicating MAIT cell infiltration into brain tumours (Peterfalvi et. al. 2008). However, basic questions remain regarding MAIT cell responses to tumour cells, particularly within the tumour microenvironment prompting us to investigate the role of MAIT cells in brain cancer.

Using in vivo models of glioblastoma (GBM), we demonstrate that survival is reduced in MR1-/- mice, implying a protective role for MAIT cells in this context. Phenotypic analysis of tumour-infiltrating lymphocytes (TILs) indicates MAIT cells can be activated and produce cytokines in response to tumours. In vitro study of the antigen presentation capacity of the tumour cells shows GBM tumour cells are capable of presenting antigen to MAIT cells and initiating MR1-dependent activation. Further, we demonstrate successful in vivo MAIT cell expansion in the mouse brain and capacity to manipulate the phenotype of expanded MAIT cells, indicating the potential of MAIT cell-based immunotherapy. Future directions for this work include detailed study of expanded MAIT cell function and phenotype following in vivo tumour challenge, including the MR1 dependence of their response.

  1. Reantragoon, Rangsima, Lars Kjer-Nielsen, Onisha Patel, Zhenjun Chen, Patricia T. Illing, Mugdha Bhati, Lyudmila Kostenko, et al. “Structural Insight into MR1-Mediated Recognition of the Mucosal Associated Invariant T Cell Receptor.” Journal of Experimental Medicine 209, no. 4 (April 9, 2012): 761–74. https://doi.org/10.1084/jem.20112095.
  2. Rudak, Patrick T, Joshua Choi, and S M Mansour Haeryfar. “MAIT Cell‐mediated Cytotoxicity: Roles in Host Defense and Therapeutic Potentials in Infectious Diseases and Cancer.” Journal of Leukocyte Biology 104 (March 16, 2018): 473–86. https://doi.org/10.1002/JLB.4RI0118-023R.
  3. Leng, Tianqi, Hossain Delowar Akther, Carl-Philipp Hackstein, Kate Powell, Thomas King, Matthias Friedrich, Zoe Christoforidou, et al. “TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions.” Cell Reports 28, no. 12 (September 2019): 3077-3091.e5. https://doi.org/10.1016/j.celrep.2019.08.050.
  4. Zhang, Yuanyue, Jacob T. Bailey, En Xu, Kunal Singh, Marieke Lavaert, Verena M. Link, Shanti D’Souza, et al. “Mucosal-Associated Invariant T Cells Restrict Reactive Oxidative Damage and Preserve Meningeal Barrier Integrity and Cognitive Function.” Nature Immunology, November 21, 2022. https://doi.org/10.1038/s41590-022-01349-1.
  5. Peterfalvi, A., E. Gomori, T. Magyarlaki, J. Pal, M. Banati, A. Javorhazy, J. Szekeres-Bartho, L. Szereday, and Z. Illes. “Invariant V 7.2-J 33 TCR Is Expressed in Human Kidney and Brain Tumors Indicating Infiltration by Mucosal-Associated Invariant T (MAIT) Cells.” International Immunology 20, no. 12 (December 1, 2008): 1517–25. https://doi.org/10.1093/intimm/dxn111.