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Targeting KMT5C Suppresses Lung Cancer Progression and Enhances the Efficacy of Immunotherapy
Yunfeng Yuan1, Qianyu Li2, Guoquan Yan3
1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Abstract:
The immune evasion is one major challenge for cancer immunotherapy. Despite considerable advancements in immune checkpoint blockade (ICB) therapies for the advanced non-small cell lung cancer (NSCLC) patients, only a minority of patients receive long-term survival benefit. Here, this work demonstrates that lysine methyltransferase 5C (KMT5C) is a crucial promoter of the NSCLC progression and immune evasion. This work first observes that upregulation of KMT5C in NSCLC correlated with cancer progression and poor patient prognosis. Notably, KMT5C knockdown in NSCLC cells suppress tumor growth and metastasis in mice. Mechanistically, this work demonstrates that KMT5C activated the DNA repair response to inhibit the STING-IRF3 pathway, downstream type I IFN signaling, and CCL5 secretion, leading to the downregulation of CD8+ T cell infiltration and function in NSCLC, ultimately facilitating tumor immune evasion and tumor progression. Importantly, both the pharmacological inhibitor A196 and the genetic inhibition of KMT5C could synergize with anti-PD-1 therapy in the lung cancer mouse model. Clinically, high expression levels of KMT5C in patients with NSCLC are associated with a lower response rate and worse clinical outcomes to ICB therapy. Therefore, these findings identify a previously unknown functional link between KMT5C and tumor immune evasion, and demonstrate that targeting KMT5C may be a potential therapeutic approach for enhancing the efficacy of NSCLC patients to ICB therapy.
Insights
Lysine methyltransferase 5C (KMT5C) drives non-small cell lung cancer (NSCLC) progression and immune evasion. Targeting KMT5C may enhance immunotherapy response in NSCLC patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cancer immunotherapy, including immune checkpoint blockade (ICB), offers survival benefits for advanced non-small cell lung cancer (NSCLC) patients, but efficacy is limited.
- Tumor immune evasion remains a significant challenge, hindering the effectiveness of current immunotherapies.
Purpose of the Study:
- To investigate the role of lysine methyltransferase 5C (KMT5C) in NSCLC progression and immune evasion.
- To explore KMT5C as a potential therapeutic target to improve ICB therapy efficacy in NSCLC.
Main Methods:
- Correlative analysis of KMT5C expression with NSCLC progression and patient prognosis.
- In vivo studies involving KMT5C knockdown in NSCLC cells to assess tumor growth and metastasis.
- Mechanistic studies to elucidate KMT5C's role in DNA repair, immune signaling pathways (STING-IRF3, type I IFN, CCL5), and CD8+ T cell infiltration.
- Evaluation of KMT5C inhibition (pharmacological and genetic) in combination with anti-PD-1 therapy in a lung cancer mouse model.
- Clinical analysis of KMT5C expression in NSCLC patients and its association with ICB therapy response.
Main Results:
- Upregulation of KMT5C in NSCLC correlates with advanced disease and poor prognosis.
- KMT5C knockdown suppresses tumor growth and metastasis in mice.
- KMT5C activates DNA repair, inhibiting the STING-IRF3 pathway and reducing CD8+ T cell infiltration, thereby promoting immune evasion.
- Pharmacological or genetic inhibition of KMT5C synergizes with anti-PD-1 therapy in preclinical models.
- High KMT5C expression in NSCLC patients is linked to lower response rates and worse outcomes with ICB therapy.
Conclusions:
- KMT5C is a key driver of NSCLC progression and immune evasion by suppressing anti-tumor immunity.
- Targeting KMT5C represents a promising strategy to enhance the efficacy of immune checkpoint blockade therapy in NSCLC patients.
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