SCLC is an aggressive neuroendocrine cancer, accounting for 15% of lung cancer cases. It is characterized by rapid growth, early metastasis, and high mortality, claiming up to 200,000 lives annually. Metastatic disease remains the leading cause of death among SCLC patients. Although platinum-based chemotherapy achieves temporary success, most patients experience relapse with treatment-resistant forms of the disease.
Recent research has identified SCLC subgroups, revealing variations in gene activity that influence disease progression, challenging the previous notion of SCLC’s homogeneity. The metastatic potential of SCLC is associated with its low immunogenicity, including reduced expression of major histocompatibility complex (MHC) genes. Single-cell RNA analysis revealed high STAT3 expression in some SCLC subgroups. STAT3 regulates proliferation, survival, metabolism, and immune responses.
Scientists from the Cancer Research Center in Australia investigated STAT3’s role in SCLC development and metastasis, focusing on its interaction with the innate immune system via the cGAS-STING pathway and its impact on the tumor’s metastatic potential.
The study involved genetically engineered mice with the Stat3 gene deleted and human SCLC cell lines. Key research objectives included:
- The role of STAT3 in primary tumor development and metastasis.
- Immune dependency in the tumor’s metastatic potential.
- The effect of STAT3 on STING expression and type I interferon production.
STAT3 and Primary Tumor Development in SCLC
Most patients with tumors exhibit STAT3 hyperexpression or activation. Among untreated SCLC patients, high STAT3 activity correlated with better survival than low STAT3 activity, suggesting that STAT3 may suppress tumor development in SCLC.
STAT3 expression was highest in specific SCLC subgroups:
- SCLC-I: Inflammatory subtype (primarily).
- SCLC-A: Neuroendocrine subtype with high ASCL1 expression.
- SCLC-N: Neuroendocrine subtype with high NEUROD1 expression.
Deleting Stat3 in mice reduced the number and size of tumors and increased survival from 42 to 64 days. However, tumor characteristics remained unchanged: proliferative capacity was high, and cell death was low. Transplanting tumor cells showed that STAT3 did not affect tumor growth, indicating its role is limited to the early stages of tumor development. Conversely, transplanting human tumor cells with deleted Stat3 into mice increased tumor growth, confirming STAT3’s possible tumor-suppressive role in humans.
Stat3 Deletion Increases the Metastatic Potential of SCLC
Mice lacking Stat3 exhibited a significant increase in liver metastases, averaging 30 lesions, compared to control mice, which showed no metastases. Analysis of circulating tumor cells revealed that STAT3 loss within tumors facilitated their release into the bloodstream, increasing metastatic potential.
Immune-Dependent Suppression of SCLC Metastasis
The immune system’s role in suppressing metastasis was confirmed in mice with typical immune systems versus immunodeficient mice. Tumor growth rates for Stat3-deleted cells were higher in immunodeficient mice. In mice with typical immune systems, Stat3-deleted tumor cells caused more secondary liver metastases than cells with active Stat3.
However, in immunodeficient mice, the metastatic potential of Stat3-deficient and Stat3-active cells was indistinguishable; metastases developed in nearly all immunodeficient mice, indicating that immune-dependent suppression of metastasis, particularly involving STAT3, is more pronounced in mice with normal immune responses.
Stat3 deletion reduced the presence of NK cells, activated CD8+ T cells, dendritic cells, monocytes, and activated interstitial macrophages. Even in early disease stages, there was a significant increase in circulating tumor cells.
Immunodeficient mice lack T, B, and NK cells, and STAT3 deficiency in SCLC reduces the recruitment of CD8+ T cells and NK cells. Depleting NK cells in mice with typical immune systems increased liver metastases. These findings suggest that STAT3-dependent metastasis suppression involves immune responses, particularly NK cell activity.
STAT3 Is Required for STING Expression and Type I Interferon Production
STAT3 is critical for expressing STING, a key component in detecting cytosolic DNA. Stat3 loss disrupted cGAS-STING pathway activation, reducing type I interferon secretion and immune cell infiltration into the tumor.
IRF proteins are necessary for IFN secretion following activation of innate immune sensors. IRF7 is expressed at low levels until a response amplifies its expression, leading to subsequent IFN release, making IRF7 a biomarker for IFN presence.
In SCLC, Stat3 deletion impaired IFN secretion, resulting in low IRF7 expression unless cells were exposed to IFN. IRF7 expression in Stat3-deficient tumor cells reduced liver metastases. Among SCLC patients, high IRF7 expression correlated with improved survival.
Stat3 loss disrupted the cGAS-STING pathway, lowering type I IFN production and promoting metastatic spread. Re-expressing STING or IRF7 limited metastasis, underscoring IFN’s critical role in immune-dependent suppression of metastatic disease. Restoring STING expression or treating it with type I interferons reduces metastatic spread.
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Reference
A STAT3–STING–IFN axis controls the metastatic spread of small cell lung cancer
