559 Background: Myeloid immune cells such as myeloid derived suppressor cells (MDSC) and tumor associated macrophages (TAM) have been hypothesized to cause resistance to immune checkpoint blockade (ICB). This is a pressing clinical problem for patients with bladder cancer. Here we determined if we could identify immune cells associated with resistance to ICB in the BBN963 mouse model, and if we could identify therapeutic strategies to target those same suppressor immune cells from patients with bladder cancer. Methods: BBN963 subcutaneous allografts were established in C57BL6/J mice. Response to anti-PD-L1 ICB was classified as partial or complete response according to RECIST criteria. Immune cell subsets with the tumors was evaluated by gene expression profiling and flow cytometry. Peripheral blood from patients with bladder cancer was collected under an IRB-approved protocol. MDSC were purified by flow sorting (CD11b+ CD33+ HLA-DRlow/neg) and screened for viability (Annexin-V staining) after 24 hours of exposure to a panel potential MDSC inhibitors. Results: 16/22 (72%) subjects met criteria for partial or complete response, while 6/22 (28%) were classified as anti-PD-L1 non-responders. Mice in the control group had a 0/10 (0%) response to isotype control (IgG) treatment. Monocytic MDSC (CD11b+ Ly6C+) were much more frequent among the intratumoral CD45+ cells of non-responding subjects as compared to control mice. Nanostring immune panel gene expression profiling revealed that combination treatment of tumor bearing mice with anti-PD-L1 plus ibrutinib (a putative MDSC inhibitor) decreased mRNA biomarkers of tumor-infiltrating macrophages. In vitro screening of patient-derived peripheral blood mononuclear cells showed that an inhibitor of the bromodomain and extraterminal domain (BET) family BRD4 specifically decreased MDSC viability. Conclusions: Monocytic MDSC appear to be associated with resistance to anti-PD-L1 ICB in a new murine model. Analysis of MDSC from patients with bladder cancer suggests that these myeloid suppressor cells can be specifically targeted.
An Interferon Inducible Signature of Airway Disease from Gene Expression Profiling of Peripheral Blood from COPDGene
