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Tissue-resident memory CD8+ T cells promote melanoma–immune equilibrium in skin

Simone L. Park, Anthony Buzzai, Jai Rautela, Jyh Liang Hor, Katharina Hochheiser, Maike Effern, Nathan McBain, Teagan Wagner, Jarem Edwards, Robyn McConville, James S. Wilmott, Richard A. Scolyer, Thomas Tüting, Umaimainthan Palendira, David Gyorki, Scott N. Mueller, Nicholas D. Huntington, Sammy Bedoui, Michael Hölzel, Laura K. Mackay (), Jason Waithman () and Thomas Gebhardt ()
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Simone L. Park: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Anthony Buzzai: University of Western Australia
Jai Rautela: Walter and Eliza Hall Institute for Medical Research
Jyh Liang Hor: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Katharina Hochheiser: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Maike Effern: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Nathan McBain: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Teagan Wagner: University of Western Australia
Jarem Edwards: The University of Sydney
Robyn McConville: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
James S. Wilmott: The University of Sydney
Richard A. Scolyer: The University of Sydney
Thomas Tüting: University of Magdeburg
Umaimainthan Palendira: The University of Sydney
David Gyorki: Peter MacCallum Cancer Centre
Scott N. Mueller: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Nicholas D. Huntington: Walter and Eliza Hall Institute for Medical Research
Sammy Bedoui: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Michael Hölzel: University of Bonn
Laura K. Mackay: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Jason Waithman: University of Western Australia
Thomas Gebhardt: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity

Nature, 2019, vol. 565, issue 7739, 366-371

Abstract: Abstract The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication1. Clinical and experimental data suggest that the latter mode of control—termed cancer–immune equilibrium1—can be maintained for prolonged periods of time, possibly up to several decades2–4. Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses that maintain cancer–immune equilibrium in these tissue compartments remain unclear. Here, using a mouse model of transplantable cutaneous melanoma5, we show that tissue-resident memory CD8+ T cells (TRM cells) promote a durable melanoma–immune equilibrium that is confined to the epidermal layer of the skin. A proportion of mice (~40%) transplanted with melanoma cells remained free of macroscopic skin lesions long after epicutaneous inoculation, and generation of tumour-specific epidermal CD69+ CD103+ TRM cells correlated with this spontaneous disease 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 melanoma cells in the epidermal layer of the 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 that were generated before melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of TRM cells triggered tumour outgrowth in a proportion (~20%) of mice with occult melanomas, demonstrating that TRM cells can actively suppress cancer progression. Our results show that TRM cells have a fundamental role in the surveillance of subclinical melanomas in the skin by maintaining cancer–immune equilibrium. As such, they provide strong impetus for exploring these cells as targets of future anticancer immunotherapies.

Date: 2019
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DOI: 10.1038/s41586-018-0812-9

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