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

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Date
2017-11
ICR Author
Harrington, Kevin
Zaidi, Shane Haider
Melcher, Alan
Author
Kottke, T
Evgin, L
Shim, KG
Rommelfanger, D
Boisgerault, N
Zaidi, S
Diaz, RM
Thompson, J
Ilett, E
Coffey, M
Selby, P
Pandha, H
Harrington, K
Melcher, A
Vile, R
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Type
Journal Article
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Abstract
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 immunosurveillance. In the first, the role of TNFα 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 IFNγ, PD-L1hi MRD cells promoted the secretion of IL6 but minimal IFNγ, inhibiting both NK-cell and T-cell surveillance. Tumor recurrence was promoted by trauma- or infection-like stimuli inducing VEGF and TNFα, which stimulated the growth of MRD tumors. Finally, therapies that blocked PD-1, TNFα, or NK cells delayed or prevented recurrence. These data show how innate immunosurveillance mechanisms, which control infection and growth of primary tumors, are exploited by recurrent, competent tumors and identify therapeutic targets in patients with MRD known to be at high risk of relapse. Cancer Immunol Res; 5(11); 1029-45. ©2017 AACR.
URI
https://repository.icr.ac.uk/handle/internal/854
DOI
https://doi.org/10.1158/2326-6066.cir-17-0175
Collections
  • Cancer Biology
  • Radiotherapy and Imaging
Subject
Killer Cells, Natural
T-Lymphocytes
Cell Line, Tumor
Animals
Mice, Inbred C57BL
Mice, Transgenic
Reoviridae
Melanoma, Experimental
Skin Neoplasms
Neoplasm Recurrence, Local
Paclitaxel
Ganciclovir
Tumor Necrosis Factor-alpha
Antibodies
Cytokines
Immunologic Surveillance
Female
Oncolytic Virotherapy
Research team
Targeted Therapy
Translational Immunotherapy
Language
eng
Date accepted
2017-10-03
License start date
2017-11
Citation
Cancer immunology research, 2017, 5 (11), pp. 1029 - 1045

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