The combination of radiation with immune-checkpoint inhibitors was reported in some cancers to have synergic effects both locally and distally. Our aim was to assess this combined therapy on both radiated and non-radiated bladder tumors and to characterize the immune landscape within the tumor microenvironment. Murine bladder cancer cells (MB49) were injected s.c. in both flanks of C57BL/6 mice. Mice were randomly assigned to the following treatments: placebo, antiPD-L1 (4 intra-peritoneal injections over 2 weeks), radiation to right flank (10Gy in two fractions), or radiation+anti-PD-L1. Tumor digestion, flow cytometry, and qPCR were performed. Log-rank analysis was used for statistical significance. Radiation+antiPD-L1 group demonstrated statistically significant slower tumor growth rate both in the radiated and non-irradiated tumors (p<0.001). Survival curves demonstrated superior survival in the combination group compared to each treatment alone (p=0.02). Flow cytometry showed increased infiltration of immuno-suppressive cells as well as cytotoxic lymphocytes (CTL) in the radiation and combination groups (p=0.04). Ratio of immunosuppressive cells to CTL shifted in favor of cytotoxic activity in the combination arm (p<0.001). The qPCR analysis revealed downregulation of immunosuppressive genes (CCL22, IL22 and IL13), as well as upregulation of markers of CTL activation (CXCL9, GZMA and GZMB) within both the radiated and distant tumors within the combination group. Combining radiation with immune checkpoint inhibitor provided better response in the radiated tumors and also the distant tumors along with a shift within the tumor microenvironment favoring cytotoxic activity. These findings demonstrate a possible abscopal effect in urothelial carcinoma with combination therapy.
Molecular cancer therapeutics. 2019 Sep 18 [Epub ahead of print]
Alexis Rompré-Brodeur, Surashri Shinde-Jadhav, Mina Ayoub, Ciriaco A Piccirillo, Jan Seuntjens, Fadi Brimo, Jose Joao Mansure, Wassim Kassouf
Urology, McGill University Health Centre., Urologic Oncology, Research Institute of the McGill University Health Centre., Department of Microbiology and Immunology, McGill University Health Centre., Medical Physics, McGill University Health Centre., Pathology, McGill University Health Centre., Urology, McGill University Health Centre .