Sign to How Specific Fast-Growing Cancer Tumor Cells Disappear In Plain Sight

A New LJI study could lead to the development of more efficient cancer immunotherapies.

The gleam of a panther’s eyes in the somberness. The zig-zagging of a shark’s dorsal fin above the water.

Humans are regularly studying society for threats. We want the opportunity to act, to call for help, to move before crisis hits. Our cells do the same thing. The natural immune system is the body’s prime warning system. It examines cells regularly for symptoms that a dangerous mutation or pathogen could provoke disease. And what does it like to look for? Misplaced genetic material.

Nucleic acid is the structure of DNA that is supposed to be store in the cell nucleus. But, Viruses can change that. Diseases can breakout genetic matter in portions of the cell where it’s not supposed to be. Cancer cells do too.

According to Sonia Sharma, Ph.D., an assistant professor at the La Jolla Institute for Immunology (LJI), “Cancer cells suppress degraded DNA, aberrant DNA, or mislocated DNA is a warning indication to the cell. They notify the cell, ‘There’s a problem here.’ It’s like the initial ringing of the alarm clock for the immune system.”

Now Sharma and her associates have published a new Nature Immunology research explaining the method that triggers this warning system directly inside tumor cells. Their study reveals that a DAPK3, a tumor-suppressor enzyme is a crucial element of a multi-protein system that senses scattered genetic material in tumor cells, and reduces tumor germination by actuating the fierce-sounding STING pathway.

In cancer immunotherapy, the STING pathway is recognized as a crucial activator of cancer-killing T cells that hits off the body’s robust adaptive immune response. The new research explains that through STING and DAPK3, the tumor’s innate immune system plays a more prominent role in cancer immunity than previously appreciated.

“The tumor-intrinsic immune response plays a vital part in cancer immunotherapy and regular tumor germination,” says Sharma.

Tumors emerge mutations in tumor-suppressor genes that let them spread quicker than natural tissue. Discovery of the essential role that DAPK3 acts in the STING pathway highlight a discrete obstacle in cancer and cancer immunotherapy. Tumor cells can take mutations that enable them to escape the immune system by preventing cells from sensing red flags such as lost DNA.

Cancer tumor cells
Cancer cells with mutations

Sharma and her associates with the LJI Center for Cancer Immunotherapy, UC San Diego, and Max-Planck Institute of Biochemistry discovered that lack of DAPK3 enzyme or function in tumor cells seriously hampered STING activation. Their study in mouse models explains that these tumors were hidden from the innate immune system, and the scientists recognized very few cancer-targeting CD8+ “killer” T cells in DAPK3-deficient tumors. As a consequence, the lack of DAPK3 in tumors reduced responsiveness to cancer immunotherapy.

“Tumors requiring DAPK3, spread quicker in vivo as they escape the innate immune system. They are also immune to specific immunotherapy regimens, as well as combination therapies utilizing the immune checkpoint blocker anti-PD1 to target anti-tumor T cells,” says Sharma.

Pharmaceutical corporations are seeking immunotherapies to initiate STING, which is assigned to be used in combination with immune checkpoint blockers. The current conclusions highlight the value of activating STING in tumor cells themselves — to correctly set off that initial alert system.

“Tumor-intrinsic immune responses are essential,” says research co-first author Mariko Takahashi, Ph.D., a former LJI postdoctoral colleague who now works at Massachusetts General Hospital Cancer Center.

Scientists are now examining new proteins that execute a crucial role in the initial innate immune response to cancer. “There are many opponents in the tumor microenvironment,” says Takahashi.

Journal Reference:

Mariko Takahashi, Ferhat Ay, Chan-Wang J. Lio, Anaamika Campeau, Martin Steger, Matthias Mann, Mohit Jain, Sonia Sharma, and David J. Gonzalez “The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING–IFN-β pathway,” Nature Immunology. DOI: 10.1038/s41590-021-00896-3

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