A tumor's need to avoid the adaptive immune system plays a key role in the selection of tumor suppressor genes (TSGs) for inactivation, according to a study in this week's Science. During tumorigenesis, tumors must evolve to evade the immune system and do so by disrupting the genes involved in antigen processing and presentation or by upregulating inhibitory immune checkpoint genes. To gain a better understanding of this process, a team led by investigators from Harvard Medical School performed in vivo CRISPR screens in syngeneic mouse tumor models, which allowed them to examine the requirements for tumorigenesis both with and without adaptive immune selective pressure. In each tumor type examined, they found a pronounced overlap between adaptive immune system-specific hits and the genes that are among the most frequently mutated in human tumors. "Our results demonstrate that loss of a large number of TSGs can contribute to immune evasion, increasing our understanding of tumor biology," the study's authors write. "It will be important to determine whether mutation of these TSGs can serve as biomarkers for immune modulating therapies." Additionally, establishing isogenic lines with expression or knockout of immune system adaptation TSGs will allow the study of we can study how a particular TSG changes the tumor's interaction with the immune system to evade it, which could lead to new therapies that restore immune recognition of cancer.
A previously uncharacterized driver of genomic instability and inflammation in cancer is reported in Science Advances this week. DNA alterations such as nucleotide changes and chromosomal rearrangements are a hallmark of most human cancers, often correlating with patient prognosis and therapy selection, but the underlying mechanisms of genomic instability in cancer is poorly understood. In the study, a group led by Case Western Reserve University researchers identify the cytoplasmic unconventional Myosin X (MYO10) as a regulator of genomic instability, showing that it is upregulated in both human and mouse tumors and that its expression level impacts tumor progression and response to immune therapy. The scientists also find that MYO10 and its overexpression creates an inflammatory tumor microenvironment that leads to T cell exhaustion, which promotes tumor growth. Meanwhile, inhibiting inflammation or disrupting MYO10 significantly suppressed tumor growth in mouse models of breast cancer.