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Cancer Immunology, Immunotherapy

, Volume 63, Issue 10, pp 1009–1021 | Cite as

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

  • Sungjune Kim
  • Rupal Ramakrishnan
  • Sergio Lavilla-Alonso
  • Prakash Chinnaiyan
  • Nikhil Rao
  • Erin Fowler
  • John Heine
  • Dmitry I. GabrilovichEmail author
Original Article

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.

Keywords

Radiation therapy Immune therapy CTLs Autophagy Melanoma 

Abbreviations

3MA

3-Methyladenine

ATG5

Autophagy protein 5

ATG16L1

Autophagy-related protein 16-1

CTL

Cytotoxic T lymphocyte

CTLA4

Cytotoxic T lymphocyte antigen 4

DAMP

Damage-associated molecular pattern

DC

Dendritic cell

GrzB

Granzyme B

Gy

Gray

IGFII

Insulin-like growth factor II

iNOS

Inducible nitric oxide synthase

LAMP2

Lysosome-associated membrane protein 2

LLC

Lewis lung cancer

LC3

Microtubule-associated protein 1A/1B-light chain 3

MPR

Mannose-6-phopsphate receptor

PD-L1

Programmed death-ligand 1

shRNA

Short hairpin RNA

siRNA

Small interfering RNA

TAX

Taxol

TGN

Trans-golgi network

TLR

Toll-like receptor

XRT

Radiation therapy

Notes

Acknowledgments

We thank Dr. Jeffrey Weber for critical reading of the manuscript. This work was supported in part by pilot funds from Donald A. Adam Comprehensive Melanoma Research Center at H. Lee Moffitt Cancer Center and by NIH grant CA168536 to Dmitry I. Gabrilovich. This work was supported in part by microscopy core of H. Lee Moffitt Cancer Center.

Conflict of interest

Authors declare no conflicts of interests.

Supplementary material

262_2014_1573_MOESM1_ESM.pdf (100 kb)
Supplementary material 1 (PDF 99 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sungjune Kim
    • 1
  • Rupal Ramakrishnan
    • 1
  • Sergio Lavilla-Alonso
    • 2
  • Prakash Chinnaiyan
    • 1
  • Nikhil Rao
    • 1
  • Erin Fowler
    • 1
  • John Heine
    • 1
  • Dmitry I. Gabrilovich
    • 2
    Email author
  1. 1.H. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  2. 2.The Wistar InstitutePhiladelphiaUSA

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