The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that
hypoxia-induced resistance of lung
tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on
tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by
siRNA targeting of either
beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic
tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted
tumor cells was found to be associated with the inhibition
Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the
ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10
melanoma tumor cells indicated that depletion of
beclin1 resulted in an inhibition of B16-F10
tumor growth and increased
tumor apoptosis. Moreover, in vivo inhibition of autophagy by
hydroxychloroquine in B16-F10
tumor-bearing mice and mice vaccinated with
tyrosinase-related protein-2 peptide dramatically increased
tumor growth inhibition. Collectively, this study establishes a novel functional link between
hypoxia-induced autophagy and the regulation of
antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo
tumor growth.