Schlemm’s canal is a lymphatic-like vessel in the eye that is critical for proper drainage of aqueous humor. Glaucoma results from increased intraocular pressure due to decreased aqueous humor outflow from the eye; therefore, strategies to enhance Schlemm’s canal function have potential to relieve glaucoma symptoms. In this episode, Gou Young Koh, Jaeryung Kim, and Dae-Young Park investigate factors that underlie the maintenance and integrity of Schlemm’s’ canal. Their work reveals that that angiopoietin/Tie2 signaling is essential for Schlemm’s canal function and integrity. Importantly, increasing Tie2 activity with an agonist antibody restored Schlemm’s canal function and reduced glaucoma phenotypes in mouse models, suggesting Tie2 activation be further explored as a therapeutic strategy for reducing intraocular pressure.
Although anti-VEGF therapies are commonly used to treat macular degeneration, these angiogenesis inhibitors have also been approved to target tumor growth and metastasis in several cancers. Because tumors depend on access to circulating blood to grow and metastasize, preventing angiogenesis may limit cancer progression. The success of anti-VEGF therapies in cancer has been limited, however, due to the ability of tumors to rapidly develop treatment resistance.
This week in the JCI, a study led by Dai Fukumura at Harvard Medical School and Massachusetts General Hospital has determined that immunosuppressive effects of non-classical Ly6Clo monocytes contribute to resistance against anti-VEGF therapies in mouse models of colorectal cancer. Researchers observed that treating colorectal tumors with VEGF inhibitors led to elevated expression of the chemokine CX3CL1. Elevations in CX3CL1 levels enhanced the recruitment of Ly6Clo monocytes into tumors, which in turn increased neutrophil migration and immunosuppressive IL-10 production within the tumor. Preventing Ly6Clo monocyte infiltration or blocking the receptor for CX3CL1 on monocytes improved the outcome of anti-VEGF therapies in the murine models. Together, these findings reveal a previously undescribed immunosuppressive function for Ly6Clo monocytes that plays a critical role in the development of treatment resistance to anti-VEGF therapies.
In the highlighted video: Jung et al. used real-time in vivo imaging to determine that CX3CL1/CX3CR1 signaling is required for Ly6Clo monocyte recruitment into tumors. The video visualizes Ly6Clo CX3CR1-expressing monocytes (green) flowing, rolling, and crawling through a blood vessel (red) as they infiltrate tumors. A rolling monocyte is observed beginning in the lower left corner, while a flowing monocyte is seen quickly moving through the upper left quadrant of the image.
Anti-PD-1 therapy with inhibitors such as pembrolizumab has proven beneficial for multiple types of cancers. Not all patients respond to PD-1 blockade; therefore, strategies to better predict individual response to anti-PD-1 would be of great clinical benefit. In this episode, Terri McClanahan and Jared Lunceford discuss their work, which has led to the identification of a gene expression profile that correlates with clinical response to pembrolizimab. Importantly, the presence of this T cell-inflamed gene expression profile in patients prior to treatment was shown to be indicative of response in multiple cohorts and cancer types.
The accumulation of macrophages with a proinflammatory phenotype in adipose tissue is a driver of obesity-associated metabolic disease. While adipose tissue macrophages are found in the lean state, these cells have an alternatively activated (M2) phenotype. In this episode, Tamás Röszer and colleagues demonstrate that adipose tissue macrophages express a receptor for the appetite-reducing neuropeptide FF and that and that neuropeptide FF promotes M2 activation and proliferation. Additionally, obesity was associated with reduced levels of circulating neuropeptide FF. Together, the results of this study reveal an important role for neuropeptide FF in maintaining metabolically beneficial macrophages in adipose tissue.
In 2012, the JCI’s Editor in Chief Howard Rockman proposed a new series focusing on the careers of today’s most accomplished physician-scientists. Since then, Editor at Large Ushma Neill has interviewed scientists as part of the Conversations with Giants in Medicine series, including Laurie Glimcher, Huda Zoghbi, and Oliver Smithies. The interviews have revealed the diverse career paths, hidden talents, and sometimes quirky personalities of this inspirational group of researchers. To reflect on her experiences, she collected her favorite moments from the series in this highlight reel.