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Subversion of NK-cell and TNFα Immune Surveillance Drives Tumor Recurrence

Kottke, Tim, Evgin, Laura, Shim, Kevin G., Rommelfanger, Diana, Boisgerault, Nicolas, Zaidi, Shane, Diaz, Rosa Maria, Thompson, Jill, Ilett, Elizabeth, Coffey, Matt , Selby, Peter, Pandha, Hardev, Harrington, Kevin, Melcher, Alan and Vile, Richard (2017) Subversion of NK-cell and TNFα Immune Surveillance Drives Tumor Recurrence Cancer Immunology Research, 5 (11). pp. 1029-1045.

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Understanding how incompletely cleared primary tumors transition from minimal residual disease (MRD) into treatment resistant, immune-invisible recurrences has major clinical significance. We show here that this transition is mediated through the subversion of two key elements of innate immune surveillance. In the first, the role of TNFalpha changes from an antitumor effector against primary tumors into a growth promoter for MRD. Second, whereas primary tumors induced a natural killer (NK)-mediated cytokine response characterized by low IL6 and elevated IFNgamma, PD-L1hi MRD cells promoted the secretion of IL6 but minimal IFNgamma, inhibiting both NK cell and T-cell surveillance. Tumor recurrence was promoted by trauma- or infection-like stimuli inducing VEGF and TNFalpha which stimulated the growth of MRD tumors. Finally, therapies which blocked PD1, TNFalpha or NK cells delayed or prevented recurrence. These data show how innate immune surveillance mechanisms, which control infection and growth of primary tumors, are exploited by recurrent, competent tumors and identifies therapeutic targets in patients with MRD known to be at high risk of relapse.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Kottke, Tim
Evgin, Laura
Shim, Kevin G.
Rommelfanger, Diana
Boisgerault, Nicolas
Zaidi, Shane
Diaz, Rosa Maria
Thompson, Jill
Ilett, Elizabeth
Coffey, Matt
Selby, Peter
Harrington, Kevin
Melcher, Alan
Vile, Richard
Date : 15 October 2017
DOI : 10.1158/2326-6066.CIR-17-0175
Copyright Disclaimer : Copyright ©2017, American Association for Cancer Research.
Uncontrolled Keywords : Immune responses to cancer; Immunomodulation; Tumor resistance to immune response
Depositing User : Clive Harris
Date Deposited : 02 Nov 2017 10:57
Last Modified : 16 Oct 2018 02:08

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