Subversion of NK-cell and TNFα immune surveillance drives tumor recurrence

Tim Kottke, Laura Evgin, Kevin G. Shim, Diana Rommelfanger, Nicolas Boisgerault, Shane Zaidi, Rosa Maria Diaz, Jill Thompson, Elizabeth Ilett, Matt Coffey, Peter Selby, Hardev Pandha, Kevin Harrington, Alan Melcher, Richard Vile

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1029-1045
Number of pages17
JournalCancer Immunology Research
Volume5
Issue number11
DOIs
StatePublished - Nov 2017

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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    Kottke, T., Evgin, L., Shim, K. G., Rommelfanger, D., Boisgerault, N., Zaidi, S., Diaz, R. M., Thompson, J., Ilett, E., Coffey, M., Selby, P., Pandha, H., Harrington, K., Melcher, A., & Vile, R. (2017). Subversion of NK-cell and TNFα immune surveillance drives tumor recurrence. Cancer Immunology Research, 5(11), 1029-1045. https://doi.org/10.1158/2326-6066.CIR-17-0175