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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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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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description	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.
doi_str_mv	10.1038/mt.2012.19
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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
title	Radiation-inducible Immunotherapy for Cancer: Senescent Tumor Cells as a Cancer Vaccine
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