Tumor-reprogrammed resident T cells resist radiation to control tumors

• Published in: Nature communications Vol. 10; no. 1; pp. 3959 - 13
• Main Authors: Arina, Ainhoa, Beckett, Michael, Fernandez, Christian, Zheng, Wenxin, Pitroda, Sean, Chmura, Steven J, Luke, Jason J, Forde, Martin, Hou, Yuzhu, Burnette, Byron, Mauceri, Helena, Lowy, Israel, Sims, Tasha, Khodarev, Nikolai, Fu, Yang-Xin, Weichselbaum, Ralph R
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 02.09.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Cell Line, Tumor; Cell Movement - genetics; Cell Survival - genetics; Combined Modality Therapy; Functional analysis; Gene Expression Profiling - methods; Immunological memory; Immunotherapy; Immunotherapy - methods; Interferon; Interferon-gamma - immunology; Interferon-gamma - metabolism; Irradiation; Longitude; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphoid tissue; Memory cells; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neoplasms, Experimental - genetics; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; Radiation therapy; Radiation Tolerance - genetics; Radio; Radiotherapy - methods; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11906-2

Successful combinations of radiotherapy and immunotherapy depend on the presence of live T cells within the tumor; however, radiotherapy is believed to damage T cells. Here, based on longitudinal in vivo imaging and functional analysis, we report that a large proportion of T cells survive clinically relevant doses of radiation and show increased motility, and higher production of interferon gamma, compared with T cells from unirradiated tumors. Irradiated intratumoral T cells can mediate tumor control without newly-infiltrating T cells. Transcriptomic analysis suggests T cell reprogramming in the tumor microenvironment and similarities with tissue-resident memory T cells, which are more radio-resistant than circulating/lymphoid tissue T cells. TGFβ is a key upstream regulator of T cell reprogramming and contributes to intratumoral Tcell radio-resistance. These findings have implications for the design of radio-immunotherapy trials in that local irradiation is not inherently immunosuppressive, and irradiation of multiple tumors might optimize systemic effects of radiotherapy.