The innate immune system scans for signs—such as misplaced genetic material—that a pathogen or dangerous mutation could cause disease. When DNA is found in areas of the cell other than the nucleus, which can occur due to viruses or cancer, it is a danger signal. Now, researchers describe the process that triggers an alert system directly inside tumor cells. Their research shows that the tumor-suppressor enzyme DAPK3 is an essential component of a multi-protein system that senses misplaced genetic material in tumor cells, and slows tumor growth by activating the STING pathway.

This work is published in Nature Immunology in the paper, “The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway.”

Although evasion of host immunity is a hallmark of cancer, the mechanisms connecting mutations to immune escape are incompletely understood. “Cancer cells harbor damaged DNA,” said Sonia Sharma, PhD, an associate professor at the La Jolla Institute for Immunology (LJI). “Mislocated DNA or aberrant DNA is a danger signal to the cell. They tell the cell, ‘There’s a problem here.’ It’s like the first ringing of the alarm bell for the immune system.”

In cancer immunotherapy, the STING pathway is a well-known critical activator of cancer-killing T cells that kicks off the body’s powerful adaptive immune response. The new study shows that through DAPK3 and STING, the tumor’s own innate immune system plays a greater role in cancer immunity than previously appreciated.

“The tumor-intrinsic innate immune response plays an important role in natural tumor growth and cancer immunotherapy response,” said Sharma.

Through a loss-of-function screen of 1,001 tumor suppressor genes, Sharma and her colleagues identified death-associated protein kinase 3 (DAPK3) as a previously unrecognized driver of anti-tumor immunity through the stimulator of interferon genes (STING) pathway of cytosolic DNA sensing.

Discovery of the critical role that DAPK3 plays in the STING pathway highlights a distinct problem in cancer and cancer immunotherapy. Tumor cells can acquire mutations that allow them to evade the immune system by keeping cells from sensing red flags such as misplaced DNA.

The team found that loss of DAPK3 expression or function in tumor cells severely hindered STING activation. Their research in mouse models shows that these tumors were hidden from the immune system, and the researchers observed very few cancer-targeting CD8+ “killer” T cells in DAPK3-deficient tumors. As a result, loss of DAPK3 in tumors decreased responsiveness to cancer immunotherapy.

“Tumors lacking DAPK3 grow faster in vivo because they evade the immune system. They are also resistant to certain immunotherapy regimens, including combination therapies using the immune checkpoint blocker anti-PD1 to target anti-tumor T cells,” said Sharma.

More specifically, loss of DAPK3 expression or kinase activity “impaired STING activation and interferon (IFN)-β-stimulated gene induction.” The authors wrote that DAPK3 deficiency in IFN-β-producing tumors drove rapid growth and reduced infiltration of CD103+CD8α+ dendritic cells and cytotoxic lymphocytes, attenuating the response to cancer chemo-immunotherapy. In addition, they found that DAPK3 coordinated post-translational modification of STING.

The data suggest that DAPK3 is an essential kinase for STING activation that drives tumor-intrinsic innate immunity and tumor immune surveillance.

Pharmaceutical companies are pursuing immunotherapies to activate STING, which are intended to be used in combination with immune checkpoint blockers. The new findings emphasize the importance of activating STING in tumor cells themselves—to properly set off that early alert system.

“Tumor-intrinsic immune responses are important,” said study co-first author Mariko Takahashi, PhD, a former LJI postdoctoral associate who now serves at Massachusetts General Hospital Cancer Center. The researchers are now looking for additional proteins that play a role in the early innate immune response to cancer. “There are many players in the tumor microenvironment,” said Takahashi.

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