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Salk scientists find how cancer stops immune response

San Diego Union-Tribune

09-19-17

Sept. 18--Malignant tumors thrive in part by suppressing the immune system. A team led by Salk Institute scientists reports discovering one important way this takes place.

Moreover, the scientists say they have restored the immune response, inhibiting tumors in mice. They have also found evidence the mechanism is at work in cancer patients.

A study on the findings was published Monday in Nature Cell Biology. Juan Carlos Izpisúa Belmonte was senior author. Min-Zu Wu, also of the Salk Institute, was first author. Go to j.mp/hypoxmirna for the study.

Tumors make two small molecules of RNA called micoRNAs to suppress the immune response, the study said. These microRNAs turn off a sensing system called cGAS that detects the abnormal presence of DNA and alerts the immune system.

Free DNA is normally absent from cells, being bound up either in the nucleus or in mitochondria. So its presence indicates something is wrong. The cGAS system detects viral DNA, and DNA released from destroyed mitochondria.

In mice, blocking these microRNAs, called miR-25 and miR-93, slowed tumor growth. However, growth didn't slow in mice with deficient immune systems, pointing to an immune response as the cause.

Patients with invasive breast cancer were also studied for levels of these microRNAs. Those with higher levels had poorer survival rates than those with lower levels. In addition, cGAS levels demonstrated the inverse pattern -- lower levels were associated with poorer survival.

Immune cells patrol the body, searching for pathogens and for damaged cells. When they're detected, other immune cells are called out to destroy them. But cancer cells managed to evade this response.

The interior of solid tumors are hypoxic, with low levels of oxygen. Immune system cells either are absent from the interior or are prevented from calling the alarm.

Several different mechanisms are involved in this process, and the study pointed to one of them, said Omid Hamid, M.D., director of the Melanoma Center at The Angeles Clinic and Research Institute, an affiliate of Cedars-Sinai.

"I think that it just confirms what we've always known, that there are multiple different mechanisms for immune suppression," Hamid said. "There are many different components in the microenvironment that are affected."

The big question is whether this mechanism can be targeted in patients, and that isn't clear, Hamid said.

"I think it's possible," Hamid said. "I can't tell you how possible or impossible, since I don't do drug development."

However, detecting the microRNAs could be used to evaluate patient prognosis, he said.

The study is part of a bigger story of understanding the relationship between the immune system and cancer, Hamid said. That was a major topic of a conference just held by the European Society of Medical Oncology.

"The main gist of it was the promise of immune therapy, and the fact that it doesn't work for everyone, and finding out why it doesn't work for certain tumors," Hamid said. "That is most likely because each tumor is different in its immunosuppressive environment."

The study pointed to the cGAS system as possibly a better target for therapy than the microRNA molecules. Izpisúa Belmonte said going after the microRNAs would be "complicated".

"We observed consistent repression of cGAS by hypoxia in different cell types, although miR-25/93 is probably not essential for this effect in every case," the study found. The cGAS system is known to be activated by molecules called type I interferons, or IFNs, the study said.

"Thus, we conclude that the repression of cGAS IFN signaling in tumor cells is a critical event during cancer progression, indicating a critical role for hypoxia-induced cell-intrinsic immune tolerance in the development of tumors."

Funding for the study came from the Razavi Newman Integrative Genomics and Bioinformatics Core Facility; the National Institutes of Health and National Cancer Institute; the Chapman Foundation and the Helmsley Charitable Trust; the G. Harold and Leila Y. Mathers Charitable Foundation; The Moxie Foundation and UCAM.

For further reading

Cancer cells cooperate to resist therapy, UCSD study finds

Immunotherapy means options, results in cancer fight

Mouse study finds extra oxygen may spur tumor-fighting cells

The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1

Upregulation of microRNA-25 associates with prognosis in hepatocellular carcinoma

bradley.fikes@sduniontribune.com

(619) 293-1020

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