Project description:Recently, immune checkpoint inhibitors (ICIs) have been approved as first line and second-line therapies for individuals with advanced renal cell carcinoma (RCC) who developed a resistance to anti-angiogenic therapies. It remains unknown how ICIs efficacy is affected by the development of resistance to anti-angiogenic inhibitors. Thus, our goal is to evaluate transcriptomic and metabolic effects after ICI therapy of sunitinib-resistant RCC and compare the efficacy of ICIs between naïve and sunitinib-resistant RCC.
Project description:Angiogenesis-inhibitor (AI) drugs targeting vascular endothelial growth factor (VEGF) signalling to the endothelial cell (EC) are used to treat various cancers types. However, primary or secondary resistance to therapy is common. Clinical and pre-clinical studies suggest that other alternative pro-angiogenic factors are up-regulated after VEGF-pathway inhibition. Therefore, identification alternative pro-angiogenic pathway(s) is critical for the development of more effective anti-angiogenic therapy. Here we study the role of apelin as a pro-angiogenic G-protein coupled receptor (GPCR) ligand in tumor growth and angiogenesis. We applied single-cell RNA-sequencing to Mouse Lewis lung carcinoma (LLC1) or B16F10 mouse melanoma cell lines (1 X 106) implanted subcutaneously into the flanks of 12 weeks old Apln-/y or littermate control mice in combination with sunitinib or control (vehicle) treatment. We found apelin loss reduced angiogenic sprouting and tip cell marker gene expression in comparison to the sunitinib-alone treated mice and prevented EC tip cell differentiation.
Project description:Glioblastoma (GBM) exhibits significant molecular heterogeneity leading to variable treatment responses. Despite multimodal therapies, prognosis remains poor, highlighting the need for personalized approaches targeting the tumor immune microenvironment (TIME). Using single-cell RNA sequencing, multiplex immunohistochemistry, and orthotopic mouse models, we characterized distinct TIME subtypes and evaluated responses to anti-angiogenic immunotherapy and myeloid-targeting approaches. We identified three TIME subtypes: TIME-low (immune-excluded with abnormal vasculature), TIME-med (immune-infiltrated with functional T cells), and TIME-high (heavily infiltrated with immunosuppressive myeloid cells and anergic T cells). TIME-low GBMs responded transiently to anti-angiogenic immunotherapy with immunostimulatory T cell shifts, while anti-angiogenic therapy was ineffective in TIME-high GBMs due to immunosuppressive myeloid cells. CD40 agonist treatment worsened outcomes in TIME-high GBMs by increasing immunosuppressive cells and reducing NK recruitment. Conversely, PI3Kγ/δ inhibition combined with anti-angiogenic immunotherapy modestly extended survival in TIME-high tumors. Our study reveals that GBM subtypes require tailored therapeutic strategies, with TIME classification potentially predicting treatment responses and TIME-high tumors requiring myeloid reprogramming to overcome immunosuppression.
