To further enhance systemic antitumor T cell responses, Onyshchenko et al. evaluated the addition of a long-acting CD122-targeted IL-2 complex to localized, hypofractionated radiation therapy and anti-PD-1. In two mouse tumor models, the triple combination triggered proliferation of tumor-specific CD8+ T cells primarily in extratumoral compartments by expanding stem-like CXCR3+ CD8+ T cells >50-fold in blood. The abscopal effect and survival against distal non-irradiated tumors were improved with the triple treatment, and were dependent on CXCR3+ CD8+ T cells. In addition, blood-derived CD8+ T cells from triple-treated mice showed significant antitumor effects after adoptive transfer.
Contributed by Katherine Turner
ABSTRACT: Combination of radiation therapy (RT) with immune checkpoint blockade can enhance systemic anti-tumor T cell responses. Here, using two mouse tumor models, we demonstrate that adding long-acting CD122-directed IL-2 complexes (IL-2c) to RT/anti-PD1 further increases tumor-specific CD8(+) T cell numbers. The highest increase (>50-fold) is found in the blood circulation. Compartmental analysis of exhausted T cell subsets shows that primarily undifferentiated, stem-like, tumor-specific CD8(+) T cells expand in the blood; these cells express the chemokine receptor CXCR3, which is required for migration into tumors. In tumor tissue, effector-like but not terminally differentiated exhausted CD8(+) T cells increase. Consistent with the surge in tumor-specific CD8(+) T cells in blood that are migration and proliferation competent, we observe a CD8-dependent and CXCR3-dependent enhancement of the abscopal effect against distant/non-irradiated tumors and find that CD8(+) T cells isolated from blood after RT/anti-PD1/IL-2c triple treatment can be a rich source of tumor-specific T cells for adoptive transfers.
Author Info: (1) Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany. Laboratory of B
Author Info: (1) Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany. Laboratory of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics of NASU, Kyiv, Ukraine. German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. (2) Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany. German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. (3) Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany. (4) Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. (5) Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. (6) Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. (7) Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. gabriele.niedermann@uniklinik-freiburg.de. German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany. gabriele.niedermann@uniklinik-freiburg.de. German Cancer Research Center (DKFZ), Heidelberg, Germany. gabriele.niedermann@uniklinik-freiburg.de.
