Tumor-reprogrammed resident T cells resist radiation to control tumors

Ainhoa Arina (), Michael Beckett, Christian Fernandez, Wenxin Zheng, Sean Pitroda, Steven J. Chmura, Jason J. Luke, Martin Forde, Yuzhu Hou, Byron Burnette, Helena Mauceri, Israel Lowy, Tasha Sims, Nikolai Khodarev, Yang-Xin Fu and Ralph R. Weichselbaum ()
Additional contact information
Ainhoa Arina: The University of Chicago
Michael Beckett: The University of Chicago
Christian Fernandez: The University of Chicago
Wenxin Zheng: The University of Chicago
Sean Pitroda: The University of Chicago
Steven J. Chmura: The University of Chicago
Jason J. Luke: The University of Chicago
Martin Forde: The University of Chicago
Yuzhu Hou: The University of Chicago
Byron Burnette: The University of Chicago
Helena Mauceri: The University of Chicago
Israel Lowy: Regeneron Pharmaceuticals
Tasha Sims: Regeneron Pharmaceuticals
Nikolai Khodarev: The University of Chicago
Yang-Xin Fu: University of Texas Southwestern
Ralph R. Weichselbaum: The University of Chicago

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11906-2

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