Abstract
Radiation therapy induces immunogenic cell death, which can theoretically stimulate T cell priming and induction of tumor-specific memory T cell responses, serving as an in situ vaccine. In practice, this abscopal effect is rarely observed. We use two mouse models of pancreatic cancer to show that a single dose of stereotactic body radiation therapy (SBRT) synergizes with intratumoral injection of agonistic anti-CD40, resulting in regression of non-treated contralateral tumors and formation of long-term immunologic memory. Long-term survival was not observed when mice received multiple fractions of SBRT, or when TGFβ blockade was combined with SBRT. SBRT and anti-CD40 was so effective at augmenting T cell priming, that memory CD8 T cell responses to both tumor and self-antigens were induced, resulting in vitiligo in long-term survivors.
Keywords:
CD40; abscopal effect; immunotherapy; pancreatic cancer; radiotherapy; vitiligo.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antineoplastic Agents, Immunological / pharmacology*
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CD40 Antigens / antagonists & inhibitors*
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CD40 Antigens / immunology*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cancer Vaccines / immunology*
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Cell Line, Tumor
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Combined Modality Therapy
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Disease Models, Animal
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Dose-Response Relationship, Radiation
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Drug Evaluation, Preclinical
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Female
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Immunotherapy
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / metabolism
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Mice
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Molecular Targeted Therapy
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Pancreatic Neoplasms / diagnosis
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Pancreatic Neoplasms / immunology*
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Pancreatic Neoplasms / mortality
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Pancreatic Neoplasms / therapy
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Radiation, Ionizing*
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Radiosurgery
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Treatment Outcome
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Antineoplastic Agents, Immunological
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CD40 Antigens
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Cancer Vaccines