Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma

Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and anti-angiogenic therapy is the current mainstay of treatment. RCC patients develop innate or adaptive resistance to anti-angiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between anti-angiogenic therapy and tumor immune microenvironment, and determined their impact on clinical outcome. We found that anti-angiogenic therapy-treated RCC primary tumors demonstrated increased infiltration of CD4(+) and CD8(+) T lymphocytes, which was inversely related to patient overall survival (OS) and progression-free survival (PFS). Furthermore, specimens from patients treated with anti-angiogenic therapy showed higher infiltration of CD4(+)FOXP3(+) regulatory T cells (Treg) and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that anti-angiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to anti-angiogenic therapy, and will guide the development of combination therapy with PD-1/PD-L1 blocking agents

Low-Frequency Type-II Radio Detections and Coronagraph Data Employed to Describe and Forecast the Propagation of 71 CMEs/Shocks

The vulnerability of technology on which present society relies demands that a solar event, its time of arrival at Earth, and its degree of geoeffectiveness be promptly forecasted. Motivated by improving predictions of arrival times at Earth of shocks driven by coronal mass ejections (CMEs), we have analyzed 71 Earth-directed events in different stages of their propagation. The study is primarily based on approximated locations of interplanetary (IP) shocks derived from type II radio emissions detected by the Wind/WAVES experiment during 1997-2007. Distance-time diagrams resulting from the combination of white-light corona, IP type II radio, and in situ data lead to the formulation of descriptive profiles of each CME's journey toward Earth. Furthermore, two different methods to track and predict the location of CME-driven IP shocks are presented. The linear method, solely based on Wind/WAVES data, arises after key modifications to a pre-existing technique that linearly projects the drifting low-frequency type II emissions to 1 AU. This upgraded method improves forecasts of shock arrival time by almost 50%. The second predictive method is proposed on the basis of information derived from the descriptive profiles, and relies on a single CME height-time point and on low-frequency type II radio emissions to obtain an approximate value of the shock arrival time at Earth. In addition, we discuss results on CME-radio emission associations, characteristics of IP propagation, and the relative success of the forecasting methods.Comment: Solar Physics; Accepted for publication 2015-Apr-2