Abstract
Introduction: Many human cancers, including microsatellite stable (MSS) colorectal cancers (CRC), are resistant to immunotherapies including T-cell checkpoint inhibitors (CPIs). Stereotactic body radiotherapy (SBRT) has shown some promise in improving systemic immune responses to CPIs in preclinical studies although results from clinical trials have been modest. Several classes of radiosensitizers, including PARP and HDAC inhibitors, can enhance responses to CPIs by modulating the tumor microenvironment towards a more “immunogenic” phenotype. We hypothesize that combining immune-modulating radiosensitizers with SBRT will improve the susceptibility of non-immunogenic tumors to immune therapies like CPIs. In the present study, we screened candidate radiosensitizers in syngeneic CRC models and assessed the effects of radiosensitizers and SBRT on surface immunogenic proteins including MHC-1 and PDL-1.
Methods: Murine CT26 and MC38 CRC cells were treated with various doses of ABT-888 (a PARP inhibitor), MS-275 (an HDAC inhibitor), IPI-549 (a PI3Kγ inhibitor), or VE-821 (an ATR inhibitor), and alone and in combination with a single fraction of radiation (0-8 Gy). Radiation survival curves were generated using a linear quadratic model and the IC10 (dose of radiation yielding 10% cell survival) was determined. The sensitizer enhancement ratio (SER) was calculated as the ratio of the IC10 with drug/IC10 radiation alone. Surface localization of MHC-1 and PDL-1 were quantified using FLOW cytometry 24 hours after treatment with radiation +/- ABT-888 pretreatment.
Results: ABT-888 and VE-821 both sensitized CT26 and MC38 cells to ionizing radiation which was more pronounced with ABT-888. MS-275 sensitized CT26 but not MC28 cells and IPI-549 did not sensitize either line to ionizing radiation. Radiation dose-dependently increased MHC-1 and PDL-1 surface localization in both cell lines. Maximal stimulation of both MHC-1 and PDL-1 was observed after 8 Gy which increased both markers by a factor of 1.8-2.0 compared to untreated cells. ABT-888 pretreatment significantly increased surface localization of both markers following 8 Gy (2.5-2.9-fold increase compared to untreated cells) but not lower doses of radiation.
Conclusions: ABT-888 potentiates alterations in surface localization of immunogenic proteins of cancer cells following SBRT-equivalent doses of radiation. These data suggest that radiosensitizers like ABT-888 should be investigated for the potential to improve systemic immune responses.
Citation Format: Steven N. Seyedin, Vivian N. Pham, Michael Petronek, Bryan G. Allen, Joseph M. Caster. Combining stereotactic body radiation and PARP inhibitors to enhance tumor immunogenicity of colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 534.
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