Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8+ PD1+ and CD8+ Siglec-7+/Siglec-9+ T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8+ T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.
27 January 2011 in Earth Surface Processes and Landforms
Characterization of three‐dimensional (3D) airflow remains elusive within a variety of environments and is particularly challenging over complex dune topography. Previous work examining airflow over and in the lee of dunes has been restricted to two‐dimensional studies and has concentrated on dune shapes containing angle of repose lee sides only. However, the presence of vegetation in coastal dunes creates topographic differences and irregular shapes that interfere with flow separation at the crest and significantly modify lee‐side airflow patterns and potential transport. This paper presents the first 3D field characterization of airflow patterns at the lee side of a subaerial dune. Flow information was obtained using an array of 3D ultrasonic anemometers deployed over a beach surface during seven offshore wind events. Data were used to measure cross‐shore and alongshore lee‐side airflow patterns using the three dimensions of the wind vector. Distances to re‐attachment were similar to previous studies, but the range of transverse incident wind directions resulting in flow separation (0+/−35°) was almost twice that previously reported (0+/−20°). Airflow reversal took place with winds as slow as 1 m s−1. Transverse offshore winds generated areas of opposing wind directions both within the reversed zone and beyond re‐attachment, contrary to consistent deflection in only one direction found in transverse desert dunes. Patterns of flow convergence‐divergence have been reported in fluvial studies. However, while convergence was associated with weak reversal in fluvial settings, it appeared to be related to strong flow reversal here and could be produced by pressure differentials at the dune crest.