Tumor-reprogrammed resident T cells resist radiation to control tumors

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.

The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy

“…Meanwhile, another group recently found that a substantial amount of intratumoral CD8 T cells were preserved up to 14 days following both SBRT and fractionated RT. Furthermore, TGF‐β blockade was shown decrease the presence of intratumoral CD8 and CD4 T cells, suggesting a radioprotective role for TGF‐β in the context of RT 109 . Additionally, recent evidence has shown that the priming and maturation of tumor‐specific CD8 T cells following DC stimulation results in robust tumor control and a decrease in negatively prognostic pathologic features in a pancreatic adenocarcinoma model 110 .…”

Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations

“…Conversely, lower doses given in fractions (18 × 2 Gy or 5 × 2 Gy) have also been shown to increase PD-L1 expression and may result in earlier expression, suggesting that further studies into optimal RT doses are required [ 109 , 110 ]. Though higher doses may induce cell death in lymphocytes, it is likely that different T-cell populations exhibit differing sensitivities to RT, as Trm population have been demonstrated to increase in proportion following local irradiation of solid tumours [ 111 , 112 ]. IFNγ, which is found at greater levels within the irradiated tumour than at secondary sites, can also mediated T-cell survival post RT, suggesting targeting multiple tumour sites could increase the efficacy of immune responses [ 111 , 113 , 114 ].…”

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

“…A murine study using MC38 and B16 cell line xenograft models has recently implied that draining-lymph-node irradiation inhibits the induction of CD8 T-cell mediated immunity when checkpoint inhibition and radiotherapy are combined [148]. This is corroborated by the observation, that intratumoral T-cells of murine tumors withstand radiation much more effectively than T-cells in healthy tissue [71]. These results are of particular interest to radiation oncologists designing combined radio-and immunotherapeutic interventions.…”

“…Conversely, depletion of adaptive effector cells has been postulated as a concern in radiation therapy. In a recent report, Arina et al [71] suggested the existence of highly radio-resistant CD8 positive cytotoxic T-cells in the tumor microenvironment, resisting both multiple low dose (5 Gy) and a single high dose (20 Gy) of radiation in a murine model. Even after radiation, these cells retained activity and motility.…”