Abstract
More than 70% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7–H3), a potential immune checkpoint family member. Several studies have shown that high CD276 expression in cancer cells correlates with a poor clinical prognosis. This has been associated with the presence of lower tumor infiltrating leukocytes. Among those, tumor-associated macrophages can comprise up to 50% of the tumor mass and are thought to support tumor growth through various mechanisms. However, a lack of information on CD276 function and interaction partner(s) impedes rigorous evaluation of CD276 as a therapeutic target in oncology. Therefore, we aimed to understand the relevance of CD276 in tumor-macrophage interaction by employing a 3D spheroid coculture system with human cells. Our data show a role for tumor-expressed CD276 on the macrophage recruitment into the tumor spheroid, and also in regulation of the extracellular matrix modulator PAI-1. Furthermore, our experiments focusing on macrophage-expressed CD276 suggest that the antibody-dependent CD276 engagement triggers predominantly inhibitory signaling networks in human macrophages.
Highlights
More than 70% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7–H3), a potential immune checkpoint family member
Multiple studies suggest a possible connection between poor clinical prognosis in patients with high CD276 expression on tumor cells and lower tumor infiltrated lymphocytes such as CD8+ T cells, which implies an immune-modulatory role of CD27619–22
Global transcriptome analysis revealed that 55 genes were differentially regulated in H CT116CD276KO cells compared to HCT116WT cells
Summary
More than 70% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7–H3), a potential immune checkpoint family member. Several studies have shown that high CD276 expression in cancer cells correlates with a poor clinical prognosis. This has been associated with the presence of lower tumor infiltrating leukocytes. Multiple studies suggest a possible connection between poor clinical prognosis in patients with high CD276 expression on tumor cells and lower tumor infiltrated lymphocytes such as CD8+ T cells, which implies an immune-modulatory role of CD27619–22. Analysis of tissue sections obtained from colorectal cancer patients indicated a positive correlation between CD276 expression on tumor cells and CD68+ tumor associated macrophages (TAM) infiltration[20]. Our data suggest that tumor-expressed CD276 is involved in regulating the recruitment of tumor-associated macrophages and provide insights, for the first time, in signaling mediated by CD276 in macrophages
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