Jagodinsky et al. used brachytherapy to deliver a spatially heterogeneous RT dose (2 to 30 gray) to syngeneic tumors in mice to reap the breadth of dose-dependent effects of RT on the TME. RT heterogeneity induced differences in immune-related gene expression and infiltrating immune cell populations. The in situ vaccine response elicited by heterogenous RT was CD4+ and CD8+ T cell-dependent, and promoted the clonal expansion of effector CD8+ T cells. Combination with dual ICB generated more potent antitumor responses in distant, non-irradiated tumors compared to any homogeneous dose.
Contributed by Ute Burkhardt
ABSTRACT: Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.
Author Info: (1) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. Department of Radiation Oncology, Stanford University, Stanf
Author Info: (1) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA. (2) Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA. Sage Bionetworks, 2901 Third Ave. Suite 330, Seattle, WA 98121, USA. (3) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (4) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (5) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (6) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (7) Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA. (8) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (9) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (10) Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA. (11) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (12) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (13) Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA. (14) Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, NE Glisan St., Portland, OR 97213, USA. Oregon Clinic, Portland, OR 97232, USA. (15) Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, NE Glisan St., Portland, OR 97213, USA. (16) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (17) Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA. Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (18) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
