E. Gkika1, E. Firat2, S. Adebahr3, E. Graf4, I. Popp5, A. Eichhorst6, G. Radicioni7, S. K. B. Spohn8, N. H. Nicolay9, S. Kirste10, A. Rimner11, S. S. Lo12, G. Niedermann13, G. D. Duda14, and A. Grosu13; 1Department of Radiation Oncology, University Medical Center Freiburg, Freiburg, Germany, 2Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany, 3Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg and German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ) Heidelberg, Freiburg, Germany, 4Institute of Medical Biometry and Statistics, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany, 5Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany, 61 Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, DKTK-Partner Site Freiburg, Germany, Feriburg, Germany, 7Department of Radiation Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg,, Freiburg, Germany, 8Department of Radiation Oncology – University Medical Center Freiburg, Freiburg, Germany, 9Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany, 10German Cancer Consortium (DKTK), Partner Site Freiburg, Heidelberg, Germany, 11Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK), partner site DKTK-Freiburg, Freiburg, Germany, 12Department of Radiation Oncology, University of Washington/ Fred Hutchinson Cancer Center, Seattle, WA, 13German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany, 14Massachusetts General Hospital, Harvard Medical School, Boston, MA
Purpose/Objective(s): The study aimed to evaluate the immunomodulatory effects of ablative stereotactic body radiotherapy (SBRT) in patients with primary liver cancers (hepatocellular carcinoma or cholangiocarcinoma). Materials/
Methods: Fifty-three patients with liver cancer treated with SBRT were included in the prospective LAPIS study. To evaluate the effects of SBRT, immune profiling of peripheral blood was performed at the first SBRT fraction (pre-treatment), during and at the end of SBRT, and at the first (FU1) and second (FU2) follow-up. Patients were treated in 3 to 12 fractions, aiming at a BED of 100 Gy. Results: The relative CD8+ and CD4+ T cell fractions increased at the end of treatment up to the FU2, despite a significant drop in the absolute cell counts. The analysis confirmed the increased fraction of proliferating CD8+ and CD4+ T cells, including PD-1+ and PD-1– CD8+ and CD4+ T cells. Increased Ki67+ fractions in both, CD8+ and CD4+ cells may indicate an anti-tumoral T cell response. The T cells showed increased levels of exhaustion markers (PD-1, Tim-3, CTLA-4), and most T cells expressed PD-1. Tumor-reactive T cells have been found among PD-1 expressing T cellsAt the end of treatment there was a significant increase in activated non-exhausted PD-1+Tim-3– CD8+ and CD4+ T cells, which lasted until the FU2 for CD4+ T cells. Expression of the activation marker ICOS on CD8+ and CD4+ T cells was accordingly increased at the end of treatment up to the FU2 for CD4+ T cells. There was a significant drop of CD8+ and CD4+ T cells expressing the chemokine receptor CXCR3, important for T cell trafficking, which was more pronounced in CD4+ T cells. Expression of IFNg was increased in CD8+ and CD4+ T cells at the end of treatment up to the FU2 and was much more prominent in CD4+ T cells. TNF-a expression in CD8+ T cells was strongly increased at the end of treatment up to FU2, and GrzB expression increased in CD8+ and CD4+ T cells at FU1. The relative and absolute numbers of NK and NKT cells were strongly reduced mainly at the end of treatment up to the FU2. Nevertheless, IFN-g and TNF-a expression was strongly increased at the end of treatment and FU2 in NK cells. GrzB expression in NK cells was slightly reduced at FU2. Finally, there was also a significant increase in immunosuppressive Treg and MDSC. Conclusion: SBRT induced lymphopenia, but also lymphocyte activation and proliferation in liver cancer patients. Although T cells and NK cells showed good functionality, as indicated by the strong expression as indicated by the strong expression of IFN-g and TNF-a, there was also an increase in immunosuppressive Tregs and MDSCs after SBRT. Future studies should examine the relative impact of these changes on patient outcome and scheduling of immunotherapy.
