Researchers may have identified a novel genetic mechanism capable of making small cell lung cancer tumors more susceptible to an attack by the immune system, according to a new study published by Murayama et al in Cancer Discovery. The findings could lead to the development of new therapeutics to enhance the efficacy of immunotherapy in patients with the disease.
Background
Patients with small cell lung cancer currently have a 5-year survival rate of less than 5%. The disease causes the development of “cold” tumors that are often undetectable by the immune system, allowing them to evade the body’s natural defenses and making immunotherapy ineffective.
“[The mechanism] sensitized these tumors to immunotherapy, which is really promising, especially for small cell lung cancer—which has been quite resistant, in general, to any kind of treatment,” stressed senior study author Israel Cañadas, PhD, Assistant Professor in the Nuclear Dynamics and Cancer Research Program and a member of the Cancer Epigenetics Institute and the Center for Immunology at Fox Chase Cancer Center.
Study Methods and Results
In the new study, the researchers used the viral mimicry technique to induce a reaction in small cell lung cancer tumors that imitates a viral infection, thereby making it possible for immune cells to detect and target the cancer. Using genetic screening of lung cancer cells, the researchers found that the DHX9 gene—which is highly expressed in small cell lung cancer compared with other cancer types—was capable of suppressing double-stranded RNA levels, an immune-signaling molecule.
With genetic depletion of DHX9 in small cell lung cancer cells in the lab, double-stranded RNA levels significantly increased and immune signaling became activated. The DHX9-depleted cancer cells also accumulated large amounts of DNA-RNA hybrids called R-loops that damaged the DNA in cancer cells. Notably, DNA damage didn’t occur in healthy cells. “We saw a very dramatic decrease in cell viability. After knocking out DHX9 in the cancer cells, the cells died very quickly,” Dr Cañadas highlighted.
The researchers then tested their findings in mice with small cell lung cancer. They discovered that when they genetically depleted DHX9, tumor growth significantly decreased and the mice’s immune systems were able to recognize and attack the cancer cells.
In a follow-up study, the researchers combined DHX9 depletion with immunotherapy. “The tumors almost disappeared and survival dramatically increased in the mice,” underscored Dr. Cañadas. “We were surprised. We were expecting some response, but it was really dramatic,” he emphasized.
Conclusions
The novel discovery represented a major step toward finding new treatment options for patients with small cell lung cancer. The researchers plan to partner with a pharmaceutical company to development a DHX9 inhibitor.
“Our objective and dream will be to move this therapy to patients and see if this is a therapy that can work for small cell lung cancer and other cold tumors,” Dr. Cañadas concluded.
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
