The autophagy sensor ITPR1 protects renal carcinoma cells from NK-mediated killing.

  • Tumor Immunotherapy and Microenvironment
February 25, 2015 By:
  • Messai Y
  • Noman MZ
  • Janji B
  • Hasmim M
  • Escudier B
  • Chouaib S.

Clear cell renal cell carcinoma (ccRCC) is dominated by inactivating mutations in VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase), leading to constitutive activation of the hypoxia-inducible factors (HIFs) and induction of a hypoxia response transcription signature. Our study demonstrated that VHL mutation results in the acquisition of ccRCC resistance to NK-mediated lysis by a mechanism involving EPAS1/HIF-2alpha stabilization. More importantly we identified ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of EPAS1 and as a potent regulator of NK-mediated killing through the activation of autophagy in target cells by a signal derived from NK cells. Therefore, it is conceivable to consider EPAS1 or the autophagy sensor ITPR1 as a potential target in future therapeutic protocols that aim to improve NK cell responses in patients with RCC and other solid malignancies.

2015 Feb. Autophagy. [Epub ahead of print].
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