Some rapidly growing tumors, how to avoid the immune system?


 

Humans are well able to discern whether the eyes of a leopard glow in the dark or the wriggling fins of sharks near the surface of the water. This is because in an environment fraught with various dangers, you must be aware of the threats that are coming to survive in order to survive.


Like many animals, we need opportunities to react, move, and ask our neighbors for help before danger strikes. But the cells in our body do exactly the same thing.


Our innate endogenous immune system serves as the body's early warning system. By constantly looking at the cells, they track down signs that pathogens or dangerous mutations can cause disease. What these immune systems look for is misplaced genetic material.


Most of the components of DNA, a genetic material called nucleic acids, are hidden in the cell nucleus. But disease can change this, and viruses can penetrate cells and produce large quantities of their own genetic material. The same goes for cancer cells.


Focus on tumor-specific endogenous immune responses


Sonia Sharma, associate professor of La Jolla Institute for Immunology (LJI) in California said, Cancer cells have damaged DNA,. It's like telling the cell'there's a problem here. It's the same as the first alarm sound on the immune system.


Sharma's team published a new study in the medical journal Nature Immunology on the 25th, explaining how such an alarm system is triggered directly inside tumor cells. The research team expects the discovery to help develop effective cancer immunotherapy.


In the study, they found that a tumor suppressor enzyme called DAPK3 is an essential component of a multi-protein system that detects misplaced genetic material in tumor cells, and that the enzyme slows cancer growth by activating the STING pathway that sounds a ferocious beep. Showed the facts.


In the world of cancer immunotherapy, the STING pathway is well known as a key factor in activating T cells by assassination. These T cells play a role in triggering the body's strong adaptive immune response.


In this new study, DAPK3 and STING show that the tumor's own endogenous immune system plays a greater role in cancer immunity than previously known.


Sharma said, the tumor-specific endogenous immune response plays an important role in the natural tumor growth and cancer immunotherapy response.


Loss of DAPK3 reduces the effectiveness of cancer immunotherapy


Tumors evolve mutations in tumor suppressor genes, allowing the tumor to grow faster than normal tissue.


The discovery of the important role DAPK3 plays in the STING pathway this time highlights a clear problem with cancer and cancer immunotherapy. Tumor cells can acquire mutations that can evade the immune system by preventing them from detecting warning flags such as'cell misplaced DNA.


Sharma's team and colleagues at the LJI Cancer Immunotherapy Center, Max Planck Institute for Biochemistry, and University of California (San Diego) discovered that impaired DAPK3 expression or function in tumor cells seriously interferes with STING activation.


In this study, using an experimental mouse model, the researchers showed that these tumors were hidden beyond detection by the immune system. In addition, in DAPK3-deficient tumors, few CD8+'killer' T cells targeting cancer cells were observed. As a result, the loss of DAPK3 in tumors has been shown to reduce the responsiveness of cancer immunotherapy.


Tracking additional proteins involved in innate immunity


Sharma said, DAPK3-deficient tumors grow faster in vivo because they evade the immune system. These tumors also use the immune checkpoint blocker anti-PD1 to target anti-tumor T cells.It is resistant to certain immunotherapy, including combination therapy.


Currently, pharmaceutical companies are developing immunotherapy that activates STING, which can be used in conjunction with immune checkpoint inhibitors. This new discovery highlights the importance of activating STING in the tumor cells themselves so that the early warning system can function properly.


Dr. Mariko Takahashi, who currently works at the Massachusetts General Hospital Cancer Center said, he is the first author of the thesis and is a postdoctoral researcher at LJI. Tumor-intrinsic immune responses are important.


Dr. Takahashi said, the team is now looking for additional proteins that are involved in the early innate immune response to cancer. There are a number of people involved in the tumor microenvironment.

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