As the blueprint of life, DNA is the carrier of genetic information for human cells as well as viruses and bacteria. The immune system works to protect the body against the selfish DNA of infectious threats and cancer cells. DNA recognition is an important defense mechanism of the host immune system. The body “decorates” its DNA to distinguish it from microbial DNA and puts it in distinct compartments to avoid being contacted. In addition, DNA-digesting enzymes assist to degrade the mis-localized or non-decorated DNA to prevent its exposure to DNA sensors.
One such DNA-digesting enzyme—DNASE1L3—is being investigated by Dr. Shun Li. DNASE1L3 deficiency leads to increasing levels of anti-DNA antibodies, which work as a compensatory mechanism to clear DNA from dying cells. During tumor proliferation, DNA is released from dying cells and will be digested by DNASE1L3 or bound by anti-DNA antibodies. In the absence of DNASE1L3 and anti-DNA antibodies, uncleared DNA will be sensed by the immune receptor TLR9 and cause tumor cells to stop proliferating (i.e., become senescent), which leads to strong tumor rejection in mice.
Based on these observations, Dr. Li aims to determine how DNASE1L3 and anti-DNA antibodies suppress TLR9 sensing of tumor-derived DNA and prevent senescence-associated immune responses against tumors. Ultimately, Dr. Li's proposed research could broaden our understanding of tumor DNA clearance and sensing mechanisms. It may also facilitate the development of novel cancer immunotherapies by targeting DNASE1L3 and anti-DNA antibodies.
Projects and Grants
Anti-Tumor Immunity Unleased by Innate Immune Sensing Self-DNA
Memorial Sloan Kettering Cancer Center | All Cancers | 2018 | Ming O. Li, Ph.D.
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