Radiation-inducible Immunotherapy for Cancer: Senescent Tumor Cells as a Cancer Vaccine

Radiotherapy offers an effective treatment for advanced cancer but local and distant failures remain a significant challenge. Here, we treated melanoma and pancreatic carcinoma in syngeneic mice with ionizing radiation (IR) combined with the poly(ADP-ribose) polymerase inhibitor (PARPi) veliparib to...

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Bibliographic Details
Published in:Molecular therapy 2012-05, Vol.20 (5), p.1046-1055
Main Authors: Meng, Yuru, Efimova, Elena V, Hamzeh, Khaled W, Darga, Thomas E, Mauceri, Helena J., Fu, Yang-Xin, Kron, Stephen J, Weichselbaum, Ralph R
Format: Article
Language:English
Subjects:
Animals
Benzimidazoles - pharmacology
Cancer therapies
Cancer vaccines
Cancer Vaccines - immunology
Cancer Vaccines - therapeutic use
Cells
Cellular Senescence - drug effects
Cellular Senescence - radiation effects
Cluster analysis
Combined Modality Therapy
Cytokines
Cytokines - biosynthesis
Cytokines - immunology
Cytotoxicity
Cytotoxicity, Immunologic
DNA damage
DNA repair
Female
Gene expression
Humans
Immunotherapy
Immunotherapy - methods
Lymphocyte Activation
Melanoma
Melanoma, Experimental - immunology
Melanoma, Experimental - mortality
Melanoma, Experimental - therapy
Metastasis
Mice
Neoplasm Transplantation
Oncology
Original
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - mortality
Pancreatic Neoplasms - therapy
Poly(ADP-ribose) Polymerase Inhibitors
Radiation therapy
Radiation-Sensitizing Agents - pharmacology
Senescence
Survival Rate
T-Lymphocytes, Cytotoxic - immunology
Tumor Cells, Cultured
Tumors
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Summary:Radiotherapy offers an effective treatment for advanced cancer but local and distant failures remain a significant challenge. Here, we treated melanoma and pancreatic carcinoma in syngeneic mice with ionizing radiation (IR) combined with the poly(ADP-ribose) polymerase inhibitor (PARPi) veliparib to inhibit DNA repair and promote accelerated senescence. Based on prior work implicating cytotoxic T lymphocytes (CTLs) as key mediators of radiation effects, we discovered that senescent tumor cells induced by radiation and veliparib express immunostimulatory cytokines to activate CTLs that mediate an effective antitumor response. When these senescent tumor cells were injected into tumor-bearing mice, an antitumor CTL response was induced which potentiated the effects of radiation, resulting in elimination of established tumors. Applied to human cancers, radiation-inducible immunotherapy may enhance radiotherapy responses to prevent local recurrence and distant metastasis.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2012.19