Abstract
Preclinical studies suggest that radiotherapy (RT) elicits various effects on antitumor T-cell responses. However, systemic T-cell responses upon RT in real-world cancer patients, including those with metastatic breast cancer, are poorly characterized. This study aims to investigate the detailed dynamics of peripheral T cells upon stereotactic body radiotherapy (SBRT) in metastatic breast cancer patients. Peripheral blood samples of 32 prospectively recruited patients who received SBRT to bone metastasis of breast cancer, which were acquired at pre-SBRT (W0), 1 week after SBRT (W1), and 4 weeks after SBRT (W4), were analyzed using multi-color flow cytometry and cytometric bead array. Most patients (n = 30) received SBRT of 1 fraction (n = 16) or 3 fractions (n = 14). We also performed a subgroup analysis of 22 patients who did not start a new systemic therapy within 1 month before SBRT (new systemic Tx >1mo) to exclude the effects of systemic therapies. Peripheral PD-1+ CD8+ T cells, which are enriched for tumor-specific clonotypes, were activated with increased expression of Ki-67 at W1 compared to W0. Expression of Ki-67 on PD-1+ CD8+ T cells remained higher at W4 than W0, although it was not statistically significant. Moreover, expressions of Ki-67 and CTLA-4 on circulating regulatory T (TREG) cells were increased at W1 compared to W0. The suppressive (Foxp3hiCD45RA-) TREG cells also exhibited enhanced expressions of Ki-67 and CTLA-4 at W1. We defined immunologic responders (ImmRs) as patients with Ki-67 expression on PD-1+ CD8+ T cells at W1 greater than 1.5-times of W0, and otherwise immunologic non-responders (ImmNRs). Notably, fold changes in expressions of Ki-67 and CTLA-4 on TREG cells and proportion of suppressive TREG cells among total TREG cells at W1 over W0 were higher in ImmRs than ImmNRs. Similar phenotypical changes of T cells were observed in the subgroup analysis of the patients with new systemic Tx >1mo. The peripheral T-cell changes were not significantly different between the dose-fractionation schedules (1 fraction vs. 3 fractions) nor molecular subtypes of cancer. In patients with new systemic Tx >1mo, plasma level changes of TGF-β1, sCTLA-4, and s4-1BB at W1 compared to W0 were significantly higher in ImmRs compared to ImmNRs, while only change of s4-1BB was associated with the immunologic response. Our results suggest that circulating PD-1+ CD8+ T cells are activated upon SBRT. However, SBRT also results in the activation of circulating TREG cells, which was more prominent in patients with a significant activation of circulating PD-1+ CD8+ T cells. Alterations in plasma levels of TGF-β1, sCTLA-4, and s4-1BB are associated with the peripheral T-cell responses. Dose-fractionation schedule is not associated with the peripheral T-cell responses.
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More From: International Journal of Radiation Oncology*Biology*Physics
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