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Abstract:

Genetic changes are a hallmark of cancer but are particularly prominent in solid tumors compared to liquid tumors. Moreover, tumors that are arise in stiffer tissues show more genetic changes than tumors in softer tissues. We developed a method to visulaize a common type of genetic changes in live cells through application of gene editing, and we use the engineered cells to assess a mechano-genetics mechanism for observed scaling of cancer mutations. Such changes are in principle detectable by the immune system, but checkpoint ligands on cancer cells can passivate attack by immune cells. We describe disruption of a macrophage checkpoint that, in a combination treatment strategy, initiates  a ‘phagocytic feedback’ loop. In a widely used but challenging pre-clinical model, the approach generates durable cures and anti-tumor immunity.

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