Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation

Nat Cell Biol. 2016 Jun;18(6):632-44. doi: 10.1038/ncb3355. Epub 2016 May 16.

Abstract

Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression. MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown. Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF. Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF. Tumour-initiating cells (TICs) exhibit elevated G-CSF. MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop. Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients. These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Female
  • Granulocyte Colony-Stimulating Factor / metabolism
  • Humans
  • Mice
  • Myeloid-Derived Suppressor Cells / cytology*
  • TOR Serine-Threonine Kinases / genetics*
  • Tumor Microenvironment / genetics

Substances

  • Granulocyte Colony-Stimulating Factor
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse