February 22, 2024

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Unlocking Key Switch for Transforming ‘Cold Tumors’ in Cancer Therapy

Unlocking Key Switch for Transforming ‘Cold Tumors’ in Cancer Therapy



Unlocking Key Switch for Transforming ‘Cold Tumors’ in Cancer Therapy

Scientists have identified the “breakdown” switch of cancer cells, which could be a key target for heating up cold tumors!

Many cancers, such as pancreatic cancer, glioblastoma, and small cell lung cancer (SCLC), pose significant treatment challenges and have poor prognoses.

These are typical immune “cold tumors” with impenetrable microenvironments, making it difficult for immune interventions to be effective.

The breakthrough lies in reshaping the immune microenvironment to create favorable conditions for immune therapy. In recent years, the scientific community has proposed several new ideas in this regard.

Recently, a team of researchers from the Fox Chase Cancer Center in the United States published a groundbreaking study in the Cancer Discovery journal.

They introduced another strategy to transform the immune microenvironment of cold tumors, including SCLC.

Using CRISPR technology-based screening, the researchers discovered that inhibiting the RNA helicase DHX9 could increase the abundance of endogenous nucleic acids, such as double-stranded RNA, within cancer cells.

This creates a state similar to viral infection, activating “endogenous immunity” mechanisms, such as the interferon response, and successfully transforming cold tumors [1].

Unlocking Key Switch for Transforming 'Cold Tumors' in Cancer Therapy

Screenshot from the paper

“Creating a pattern similar to viral infection” has a more concise term in the professional field – “Viral Mimicry.” This mechanism was better elucidated only in 2015. In simple terms, under the influence and intervention of internal and external factors, such as epigenetic drugs (e.g., azacitidine, decitabine), endogenous retrotransposons within human cells may undergo abnormal transcription, leading to the production of endogenous DNA or RNA. One of the typical representatives is double-stranded RNA (dsRNA).

To the RNA receptors within human cells, the appearance of endogenous nucleic acids like dsRNA signals a viral infection. For example, endogenous retrovirus (ERV) infection can produce endogenous nucleic acids, activating the body’s innate antiviral and innate immune mechanisms, such as the interferon response, which is crucial for antiviral and anti-tumor immunity. Thus, the tumor immune microenvironment may transition from cold to hot, allowing immune therapy to take a more impactful approach [2].

However, the activation of “viral mimicry” by epigenetic factors varies in different cancers. Therefore, researchers needed to use CRISPR technology to screen for the activating switch in SCLC, with a focus on the RNA helicase DHX9. It quickly emerged as a key player, with researchers finding that SCLC had the highest expression levels of DHX9 among all cancers studied, and high DHX9 expression correlated with poor prognosis in most SCLC cell lines.

Upon knocking out DHX9 in SCLC cell lines using small guide RNA (sgRNA), researchers observed a significant accumulation of dsRNA. Under normal circumstances, DHX9 effectively unwinds them, preventing excessive levels of cytoplasmic dsRNA. However, knocking out DHX9 leaves dsRNA unattended, leading to an increase in the accumulation of double-stranded DNA (dsDNA).

Further experiments confirmed that knocking out DHX9 was sufficient to upregulate the expression of numerous inflammation and immune response-related genes, including a large number of interferon-stimulated genes (ISGs) and several innate immune markers of type I interferon response. This indicated the success of the “viral mimicry” strategy. At the same time, researchers also detected a significant increase in the expression of MHC-I molecules in SCLC cells after knocking out DHX9, and even the relatively rare expression of PD-L1 in SCLC saw a substantial upregulation.

Knocking out DHX9 also had some “unexpected joys.” Given the upregulation of DNA damage-related genes, researchers delved deeper and found that knocking out DHX9 prevented the unwinding of “R-loops,” three-stranded nucleic acids formed by the hybridization of RNA chains with DNA template chains. These accumulated more easily in cancer cells, not only increasing the genomic instability of cancer cells and enhancing the immunogenicity of cancer cells but also activating the cGAS-STING pathway. Both of these aspects are favorable for immune therapy.

Finally, researchers successfully replicated the conclusions of the earlier cell experiments in mouse experiments. Knocking out DHX9 in SCLC effectively inhibited tumor growth, induced more immune cell infiltration (such as CD8+ T cells), and elicited a robust anti-tumor immune response. Knocking out DHX9 also synergized with immune checkpoint inhibitors in treatment. In human SCLC patients, the expression level of DHX9 was negatively correlated with immune infiltration, immune response, and patient survival.

Researchers pointed out that knocking out DHX9 not only enhances anti-tumor immune response by increasing the accumulation of endogenous nucleic acids and inducing “viral mimicry” but also increases the DNA replication stress of cancer cells. Since most SCLC cells have TP53 or RB1 gene inactivation mutations, they are more sensitive to the replication stress caused by knocking out DHX9. Thus, knocking out DHX9 can effectively suppress cancer through a dual mechanism. As for the role of DHX9 in other solid tumors, further studies are needed to confirm.

Unlocking Key Switch for Transforming ‘Cold Tumors’ in Cancer Therapy


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[J]. Cancer Discovery, 2024.

[2]Chen R, Ishak C A, De Carvalho D D. Endogenous retroelements and the viral mimicry response in cancer therapy and cellular homeostasis[J]. Cancer Discovery, 2021, 11(11): 2707-2725.

(source:internet, reference only)

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