Non-classical monocytes contribute to treatment resistance against anti-VEGF cancer therapies

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 Ly6C^lo 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 Ly6C^lo monocytes into tumors, which in turn increased neutrophil migration and immunosuppressive IL-10 production within the tumor. Preventing Ly6C^lo 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 Ly6C^lo 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 Ly6C^lo monocyte recruitment into tumors. The video visualizes Ly6C^lo 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. 

Gene expression profile predicts response to pembrolizumab

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.

Neuropeptide FF acts on adipose tissue macrophages

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.

Twenty fascinating conversations

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.

Best of Conversations with Giants in Medicine

JCI Editor at Large Ushma S. Neill shares some of the best moments from the series Conversations with Giants in Medicine, 2012–2017.