Cancer Cell: Barrier to cancer immunotherapy discovered | by Jerry Carter | Oct, 2021

Jerry Carter

Stanniocalcin-1 (STC1) is a glycoprotein hormone involved in calcium/phosphate homeostasis that regulates a variety of cellular processes during normal development and tumorigenesis. After analyzing more than 1,000 genes, researchers at the University of Michigan (U-M) Rogel Cancer Center found that this glycoprotein could also be a barrier to cancer immunotherapy. Their findings were published in a paper titled “Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance” in the journal Cancer Cell.

“STC1 is an intracellular checkpoint, which works as an “eat-me” inhibitor, preventing macrophages and dendritic cells from phagocytosing dying or dead cancer cells. We believe that if we can target the STC1 pathway, the blocked signal will be released.” According to the researchers.

Immunotherapy elicits durable clinical responses in a subset of cancer patients. However, treatment resistance poses a major challenge to current immunotherapies. The researchers write, “Here, we found that STC1 expression was associated with immunotherapy efficacy and negatively correlated with patient survival across cancer types.”

Researchers first demonstrated that STC1 was associated with lower activation of T cells and poorer survival in melanoma patients receiving immunotherapy. They examined this against the Cancer Genome Atlas database and found that high levels of STC1 were associated with poorer survival in 10 different types of cancer.

STC1 is a secreted glycoprotein with an N-glycan modification site and is prevalent in a variety of tissues. The investigators constructed STC1 knockout and ectopic expression mouse models and compared the expression and role of STC1 in immunocompetent and immunocompetent mice. The results showed that ectopic expression of STC1 accelerated the growth of tumors in immunocompetent mice. The knockout phenotype interfered with tumor growth in immunocompetent mice, but not in immunodeficient phenotypes. Ninety-seven proteins bound to STC1 linkages were detected by enrichment of tumor cells after overexpression of STC1. Among the five proteins with the highest relevance, calreticulin (CRT) caught the attention as a known important phagocytic signaling protein. When expressed on the cell surface, CRT directs antigen-presenting cells to recognize and target phagocytosis. STC1 interferes with tumor immunity by linking to CRT and localizing to mitochondria, resulting in a decrease in CRT on the cell surface.

This finding suggests that targeting the interaction between STC1 and CRT may be a way to make immunotherapy more effective.

“Before activating the T cells, the tumor has already implemented the strategy, and that may be why some patients become resistant to immunotherapy: their tumors express too much STC1. When the “eat-me” signal is blocked, the antigen-presenting cells will not work.”

Targeting the interaction of STC1 and CRT inside cells is much more difficult than targeting the cell surface. The researchers are currently investigating whether they can develop a small compound that can penetrate cells and interfere with the STC1-CRT interaction.

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