Oral Presentation Melbourne Immunotherapy Network Winter Retreat 2018

Tissue-resident Memory CD8+ T Cells Promote Melanoma-immune Equilibrium in Skin (#38)

Simone L Park 1 , Anthony Buzzai 2 , Jai Rautela 3 , Katharina Hochheiser 1 , Maike Effern 1 4 , Nathan Mcbain 1 , Teagan Wagner 2 , Jarem Edwards 5 , Robyn McConville 1 , Richard Scolyer 6 , Thomas Tuting 7 8 , Umaimainthan Palendria 5 , David Gyroki 9 10 , Scott N Mueller 1 , Nicholas D Huntington 3 , Sammy Bedoui 1 , Michael Holzel 4 , Jason Waithman 2 , Laura K Mackay 1 , Thomas Gebhardt 1
  1. Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  2. Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
  3. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  4. Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
  5. Centenary Institute, University of Sydney, Sydney, Australia
  6. Melanoma Institute Australia, University of Sydney, Sydney, Australia
  7. Laboratory of Experimental Dermatology, Department of Dermatology, University of Magdeburg, Magdeberg, Germany
  8. Laboratory of Experimental Dermatology, University of Bonn, Bonn, Germany
  9. Peter MacCallum Cancer Centre, Melbourne, Australia
  10. Peter MacCallum Cancer Centre, Melbourne, Australia

The immune system can suppress tumour development by eliminating malignant cells and by preventing the outgrowth of cancer cells that resist eradication. Clinical and experimental data suggest the latter mode of control, termed cancer-immune equilibrium, can be maintained for prolonged periods of time, possibly up to several decades. Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses maintaining cancer-immune equilibrium in these tissue compartments remain elusive. Using a novel mouse model of transplantable cutaneous melanoma, we show that tissue-resident memory CD8+ T (TRM) cells promote a durable melanoma-immune equilibrium confined to the epidermal layer of skin. A proportion of mice transferred with melanoma cells remained free of macroscopic skin lesions long after inoculation and generation of tumour-specific epidermal CD69+CD103+ TRM cells correlated with this spontaneous control. By contrast, mice deficient in TRM formation were more susceptible to tumour development. Despite being tumour-free at the macroscopic level, mice frequently harboured dormant melanoma cells in the epidermal layer of skin long after inoculation, and intravital imaging revealed that these cells were dynamically surveyed by TRM cells. Consistent with their role in melanoma surveillance, tumour-specific TRM cells generated prior to melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of TRM cells from mice with occult melanomas triggered tumour outgrowth, thereby demonstrating that TRM cells can actively suppress cancer progression. Our results reveal a fundamental role of TRM cells in immune surveillance of subclinical melanomas in skin by maintaining cancer-immune equilibrium. As such they provide strong impetus for exploring TRM cells as targets of future cancer immunotherapies.