Discovery of DHX9 Paves the Way for Immunotherapy Success in SCLC

Israel Canadas, PhD

A genetic mechanism that can make small cell lung cancer (SCLC) tumors vulnerable to attack by the immune system has been discovered, according to findings from a study published in Cancer Discovery.¹

Viral mimicry is the strategy being applied. Through activating the innate immunity within cancer cells, it can turn immunologically "cold" tumors into "hot" ones. This phenomenon is a promising avenue in the treatment of SCLC and other "cold" tumors.

In the study conducted by researchers at Fox Chase Cancer Center, the mechanism sensitized tumors to immunotherapy.² This shows potential for patients with SCLC as the tumors are generally resistant to any kind of treatment and this mechanism may be used to develop drugs that would make immunotherapy effective in SCLC for the first time.

“We found that depleting DHX9 induces the formation of double-stranded RNA [dsRNA] derived from endogenous retroviral elements, provoking an antitumor immune response in ‘cold’ tumors, including SCLC. We also found that eliminating DHX9 induced the accumulation of RNA-DNA hybrids [R-loops], leading not only to an antiviral immune response but also to DNA replication stress and DNA damage in SCLC cells,” Israel Canadas, PhD, assistant professor, nuclear dynamics and cancer program at Fox Chase Cancer Center, told Targeted Oncology^TM. “Eliminating DHX9 also caused a significant decrease in tumor growth and induced a more immunogenic tumor microenvironment in SCLC mouse models, dramatically enhancing responsiveness to immune checkpoint blockade-based immunotherapy.”

illustration of Lungs, medical concept© yodiyim - stock.adobe.com

The viral mimicry technique is a method that involves generating a reaction in the cancer cells that is similar to a viral infection.¹ This attracts the attention of the immune system. By turning cold tumors “hot,” it is possible for immune cells to detect the tumors, as well as target them.

“Since resistance to cancer immunotherapy is related with the fact that many tumors are immunologically ‘cold’, we wanted to identify novel targets/mechanisms to activate innate immunity in tumor cells as a way to turn ‘cold’ tumors ‘hot’. A promising strategy to trigger antitumor immunity is inducing the accumulation of endogenous ‘virus-mimetic’ nucleic acids in cancer cells, such as dsRNAs. Thus, we performed a genetic screen of dsRNA regulators in SCLC cell lines and identified the RNA/DNA helicase DHX9 as a crucial suppressor of dsRNA in cancer cells,” explained Canadas.

Through the use of genetic screening of lung cancer cells, the DHX9 gene was shown to suppress levels of dsRNA, an immune-signaling molecule. Targeted depletion of DHX9 led the researchers to find a significant accumulation of cytoplasmic dsRNA, triggering an intrinsic response from the tumor's innate immunity. This finding demonstrates DHX9 to be a crucial regulator of the balance between immune quiescence and activation within cancer cells.

In addition, getting rid of DHX9 did not only activate the body's natural defense system, but it caused an unusual buildup of R-loops. This led to more DNA damage, increased levels of cytoplasmic DNA, and added stress to the cell replication process in SCLC. Overall, DHX9 plays a complex role in keeping genes stable and preventing excessive immune responses.

DHX9 deletion also had a profound impact on tumor growth reduction within in vivo experiments. The absence of DHX9 also led to a more immunogenic tumor microenvironment and enhanced the responsiveness to immune checkpoint blockade therapies, suggesting that by targeting DHX9, tumor progression can be delayed and the efficacy of immunotherapeutic interventions can be bolstered.

“This is the first description of the role of DHX9 on tumor immunity and the identification of a novel and promising target to induce ‘viral mimicry’ as a strategy to enhance antitumor immunity and boost cancer immunotherapy in some of the least responsive and deadliest tumors, such as SCLC. Our study opens novel therapeutic opportunities and suggest that future DHX9 inhibitors can improve the response to immunotherapy in immunologically ‘cold’ tumors,” added Canadas.

Overall, DHX9 is a promising therapeutic target for SCLCs, and targeting DHX9 holds promise for the future of cancer treatment, specifically for patients with SCLC and other genomically unstable tumors.

REFERENCES:

1. Murayama T, Nakayama J, Jiang X, et al. Targeting DHX9 triggers tumor-intrinsic interferon response and replication stress in small cell lung cancer. Cancer Discov. Published online January 8, 2024. doi:10.1158/2159-8290.CD-23-0486

2. Study finds novel mechanism for making small cell lung cancer tumors vulnerable to attack by immune system. News release. Fox Chase Cancer Center. January 12, 2024. Accessed January 17, 2024. http://tinyurl.com/5n986yyf