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

Abstract

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.

• Authors: Claire Vanpouille-Box, Julie M Diamond, Karsten A Pilones, Jiri Zavadil, James S Babb, Silvia C Formenti, Mary Helen Barcellos-Hoff, Sandra Demaria
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 11 Pg. 2232-42 (Jun 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25858148 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Neutralizing
• Antigens, Neoplasm
• Transforming Growth Factor beta

Topics

• Animals
• Antibodies, Neutralizing (therapeutic use)
• Antigens, Neoplasm (immunology)
• Breast Neoplasms (immunology, pathology, radiotherapy)
• CD4-Positive T-Lymphocytes (immunology, radiation effects)
• CD8-Positive T-Lymphocytes (immunology, radiation effects)
• Combined Modality Therapy
• Disease Models, Animal
• Female
• Humans
• Immunotherapy
• Mice
• Neoplasm Recurrence, Local (immunology, radiotherapy)
• T-Lymphocytes, Cytotoxic (immunology)
• Transforming Growth Factor beta (antagonists & inhibitors, immunology)