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Background: Radiation and co-stimulatory ligands or checkpoint inhibitors have demonstrated improved anti-tumor immunity and overall survival in preclinical animal studies. However, the results of human trials suggest we have not yet found the optimal combination. Here we demonstrate upregulation of ICOS expression on T cells following focal tumor radiation and test the hypothesis that ICOS agonism in combination with radiation will enhance the immunologic effect of radiation resulting in increased survival.
Methods: BALB/c mice bearing CT26 tumors or C57BL/6 mice bearing Panc02 tumors were treated at d14 with 20Gy CT guided radiation therapy and anti-ICOS antibody or isotype control antibody was administrated i.p. Mice were followed for overall survival to 100 days post implantation. Animals were euthanized when tumors reached 1.2cm in greatest diameter. Flow cytometry was performed using a T cell panel on fresh whole blood, PBMC, or tumor infiltrating immune cells.
Results: 24 hours following 20Gy focal radiation to a CT26 tumor there was a significant increase in the percent of circulating CD4 Treg that express ICOS in the blood (27.42% vs 18.02%, p<0.0001, n=5/group). Similarly, 7 days following radiation there was an increase in non-Treg CD4 cells expressing ICOS in the blood (7.73% vs 3.68%, p<0.0001, n=5/group) and the tumor (62.16% vs 34.04%, p=0.004, n=5/group). ICOS expression was also increased on CD8 T cells in irradiated tumors (25.34% vs 14.02%, p=0.007). In mice bearing CT26 tumors, ICOS agonist antibody was administered prior to, concurrent with, or 7 days post radiation. Concurrent administration was associated with the most significant increase in survival (50%) when compared to isotype control (0%), ICOS agonist antibody alone (10%), or radiation plus isotype (0%). In the less immunogenic Panc02 tumor model, no survival benefit was seen with radiation and ICOS therapy. However in the same model, dual PD-1 antagonism and ICOS agonism plus radiation led to a significant increase in survival when compared to all other combinations, with an increase in median survival from 46 days to 68 days, p=0.01 compared to radiation alone and was associated with a 25% long term survival.
Conclusions: ICOS is upregulated on T cells following radiation and targeting ICOS in combination with radiation is associated with improved survival. Timing appears important as the benefit is optimal when ICOS agonism is delivered concurrent with radiation rather than preceding or 7 days post-radiation. In poorly immunogenic tumors, addition of PD-1 antagonism to the combination can lead to improved survival.
Ethics Approval: Animal protocols were approved by the Earle A. Chiles Research Institute IACUC (Animal Welfare Assurance No. A3913-01). All experiments were performed in accordance with relevant guidelines and regulations.
Cancer, immunotherapy, T cells, radiation therapy, cancer immunity, ICOS
Gough, Michael J.; Bambina, Shelly; Gostissa, Monica; Harvey, Christopher; Friedman, David; and Crittenden, Marka R, "Inducible T cell Co-stimulator (ICOS) is upregulated on lymphocytes following radiation of tumors and ICOS agonism in combination with radiation results in enhanced tumor control" (2018). Society for Immunotherapy of Cancer 2018 Annual Meeting Posters. 13.