TGFβ Is a Master Regulator of Radiation Therapy-Induced Antitumor Immunity

T cells directed to endogenous tumor antigens are powerful mediators of tumor regression. Recent immunotherapy advances have identified effective interventions to unleash tumor-specific T-cell activity in patients who naturally develop them. Eliciting T-cell responses to a patient's individual...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2015-06, Vol.75 (11), p.2232-2242
Main Authors: Vanpouille-Box, Claire, Diamond, Julie M, Pilones, Karsten A, Zavadil, Jiri, Babb, James S, Formenti, Silvia C, Barcellos-Hoff, Mary Helen, Demaria, Sandra
Format: Article
Language:English
Subjects:
Animals
Antibodies, Neutralizing - therapeutic use
Antigens, Neoplasm - immunology
Breast Neoplasms - immunology
Breast Neoplasms - pathology
Breast Neoplasms - radiotherapy
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - radiation effects
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - radiation effects
Combined Modality Therapy
Disease Models, Animal
Female
Humans
Immunotherapy
Mice
Neoplasm Recurrence, Local - immunology
Neoplasm Recurrence, Local - radiotherapy
T-Lymphocytes, Cytotoxic - immunology
Transforming Growth Factor beta - antagonists & inhibitors
Transforming Growth Factor beta - immunology
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Summary:T cells directed to endogenous tumor antigens are powerful mediators of tumor regression. Recent immunotherapy advances have identified effective interventions to unleash tumor-specific T-cell activity in patients who naturally develop them. Eliciting T-cell responses to a patient's individual tumor remains a major challenge. Radiation therapy can induce immune responses to model antigens expressed by tumors, but it remains unclear whether it can effectively prime T cells specific for endogenous antigens expressed by poorly immunogenic tumors. We hypothesized that TGFβ activity is a major obstacle hindering the ability of radiation to generate an in situ tumor vaccine. Here, we show that antibody-mediated TGFβ neutralization during radiation therapy effectively generates CD8(+) T-cell responses to multiple endogenous tumor antigens in poorly immunogenic mouse carcinomas. Generated T cells were effective at causing regression of irradiated tumors and nonirradiated lung metastases or synchronous tumors (abscopal effect). Gene signatures associated with IFNγ and immune-mediated rejection were detected in tumors treated with radiation therapy and TGFβ blockade in combination but not as single agents. Upregulation of programmed death (PD) ligand-1 and -2 in neoplastic and myeloid cells and PD-1 on intratumoral T cells limited tumor rejection, resulting in rapid recurrence. Addition of anti-PD-1 antibodies extended survival achieved with radiation and TGFβ blockade. Thus, TGFβ is a fundamental regulator of radiation therapy's ability to generate an in situ tumor vaccine. The combination of local radiation therapy with TGFβ neutralization offers a novel individualized strategy for vaccinating patients against their tumors.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-14-3511