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Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice.

ABSTRACT: There is a significant body of evidence demonstrating that radiation therapy (XRT) enhances the effect of immune therapy. However, the precise mechanisms by which XRT potentiates the immunotherapy of cancer remain elusive. Here, we report that XRT potentiates the effect of immune therapy via induction of autophagy and resultant trafficking of mannose-6-phopsphate receptor (MPR) to the cell surface. Irradiation of different tumor cells caused substantial up-regulation of MPR on the cell surface in vitro and in vivo. Down-regulation of MPR in tumor cells with shRNA completely abrogated the combined effect of XRT and immunotherapy (CTLA4 antibody) in B16F10-bearing mice without changes in the tumor-specific responses of T cells. Radiation-induced MPR up-regulation was the result of redistribution of the receptor to the cell surface. This effect was caused by autophagy with redirection of MPR to autophagosomes in a clathrin-dependent manner. In autophagosomes, MPR lost its natural ligands, which resulted in subsequent trafficking of empty receptor(s) back to the surface. Together, our data demonstrated a novel mechanism by which XRT can enhance the effect of immunotherapy and the molecular mechanism of this process.

SUBMITTER: Kim S

PROVIDER: S-EPMC4330093 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice.

Kim Sungjune S Ramakrishnan Rupal R Lavilla-Alonso Sergio S Chinnaiyan Prakash P Rao Nikhil N Fowler Erin E Heine John J Gabrilovich Dmitry I DI

Cancer immunology, immunotherapy : CII 20140619 10

There is a significant body of evidence demonstrating that radiation therapy (XRT) enhances the effect of immune therapy. However, the precise mechanisms by which XRT potentiates the immunotherapy of cancer remain elusive. Here, we report that XRT potentiates the effect of immune therapy via induction of autophagy and resultant trafficking of mannose-6-phopsphate receptor (MPR) to the cell surface. Irradiation of different tumor cells caused substantial up-regulation of MPR on the cell surface i ...[more]

PMID: 24943275

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Project description:BackgroundMannose, a natural hexose existing in daily food, has been demonstrated to preferentially inhibit the progression of tumors with low expression of phosphate mannose isomerase (PMI). However, its function in thyroid cancer still remains elusive.MethodsMTT, colony formation and flow cytometry assays were performed to determine the response of thyroid cancer cells to mannose. Meanwhile, mouse models of subcutaneous xenograft and primary papillary thyroid cancer were established to determine in vivo anti-tumor activity of mannose. The underlying mechanism of mannose selectively killing thyroid cancer cells was clarified by a series of molecular and biochemical experiments.ResultsOur data demonstrated that mannose selectively suppressed the growth of thyroid cancer cells, and found that enzyme activity of PMI rather than its protein expression was negatively associated with the response of thyroid cancer cells to mannose. Besides, our data showed that zinc ion (Zn2+) chelator TPEN clearly increased the response of mannose-insensitive cells to mannose by inhibiting enzyme activity of PMI, while Zn2+ supplement could effectively reverse this effect. Further studies found that the expression of zinc transport protein ZIP10, which transport Zn2+ from extracellular area into cells, was negatively related to the response of thyroid cancer cells to mannose. Knocking down ZIP10 in mannose-insensitive cells significantly inhibited in vitro and in vivo growth of these cells by decreasing intracellular Zn2+ concentration and enzyme activity of PMI. Moreover, ectopic expression of ZIP10 in mannose-sensitive cells decrease their cellular response to mannose. Mechanistically, mannose exerted its anti-tumor effect by inhibiting cellular glycolysis; however, this effect was highly dependent on expression status of ZIP10.ConclusionThe present study demonstrate that mannose selectively kills thyroid cancer cells dependent on enzyme activity of PMI rather than its expression, and provide a mechanistic rationale for exploring clinical use of mannose in thyroid cancer therapy.

Dataset Information

Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice.

Publications

Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice.

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