Abstract LB-A008: Reversing immune checkpoint inhibitor resistance rherapy in advanced thyroid cancer

Abstract Background: Patients with advanced thyroid cancer have few treatment options and poor survival [e.g. 10% at 10 years for radioactive iodine-refractory differentiated thyroid cancer (DTC)] and immune checkpoint inhibitors (ICI) have not shown benefit in these patients. The goal of this project is to identify novel strategies to improve the efficacy of ICI therapy in thyroid cancer. Prior work showed that suppressive myeloid cells are important contributors to immune escape and ICI resistance in thyroid cancer. In addition, clinical studies have shown that the presence of MDSCs in the peripheral blood of thyroid cancer patients correlates with more advanced disease and recurrence. In melanoma, colon, and lung tumor models, the TLR9 agonist CpG can act on myeloid cells to reduce suppressive function, increase antigen presentation and augment T cell proliferation, activation, and ingress into the tumor. We hypothesized that combined ICI therapy with TLR9 agonist CpG reverse of MDSC suppression to improve anti-tumor efficacy of ICI in DTC. Methods: Mice bearing poorly differentiated BRAFV600E+ papillary thyroid cancer tumors were randomized to treatment with isotype control or ICI (anti-PD1 or anti-PDL1; 250mg/dose i.p., 2x weekly) antibodies, with or without CpG-1826 peritumorally. In addition, we tested ICI with directly conjugated CpG given intraperitoneally compared to ICI alone as a potential systemic therapy. Immune populations in tumor and spleen were evaluated using immunofluorescence, flow cytometry, and in vitro functional assays. Tumor volume was measured thrice weekly. Results: ICI treatment alone (anti-PD1 or anti-PDL1) had no effect on tumor growth compared to isotype control. There were no differences in CD44+ IFNγ+CD8+ effector T cells and CD11b+Gr1hi MDSCs in tumor-bearing mice. Interestingly, peritumoral injection of CpG with concurrent ICI treatment resulted in significantly slower tumor growth (p