Editor’s Note:
Hepatocellular carcinoma (HCC) is the most common malignant liver tumor in our country, posing a significant threat to the lives and health of our people. Presently, the treatment for advanced HCC is primarily systemic therapy based on targeted and immunotherapy. Deciding on the appropriate multi-target inhibitors and immunotherapies for combined treatment is a hot topic in current research. At the recently concluded 13th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2023), researchers from the Hong Kong Polytechnic University, China, presented a study (Abstract Number: OP-07) that reveals the mechanism of the wild-type Kras gene in HCC immune evasion. This research suggests that combining KRAS inhibitors might enhance the immunotherapeutic response in liver cancer patients, earning it the honor of an outstanding oral report. We have compiled and edited the findings of this study for our readers.
Although immune checkpoint inhibitors (ICIs) show great promise in treating HCC patients, the response rate is only around 15%. This unsatisfactory outcome can be attributed to the ability of HCC cells to evade immune surveillance. Hence, it is imperative to understand the immune evasion mechanisms of HCC.
Using an antigen-expressing C-MycOE/Tp53KO HCC mouse model, the researchers identified the critical signaling pathways in HCC immune evasion using data-independent acquisition mass spectrometry (DIA-MS) proteomics. The researchers then validated the protein function in vivo. Potential functional pathways were explored using single-cell RNA sequencing (scRNA-seq), immune mapping, protein imprinting, and multi-immune fluorescence staining.
The study discovered that the wild-type Kras gene is highly upregulated in HCC immune evasion, simultaneously activating its ligand-driven EGFR and the downstream MEK/ERK signaling pathway. Overexpression of endogenous Kras in this model leads to increased tumor burden in mice and reduced survival time, highlighting Kras signaling’s regulatory role in immune evasion.
Clinically, the wild-type Kras in HCC patients is overexpressed at both mRNA and protein levels, correlating with tumor recurrence and a lower survival rate. ScRNA-seq analysis showed that Kras overexpression could hinder dendritic cell recruitment by suppressing interferon signaling, leading to defective T-cell activity. The study suggests that the activation of Kras/MEK/ERK signaling can interfere with T-cell recognition of HCC by downregulating MHC-I driven antigen presentation.
This study reveals a new role of wild-type Kras and its signaling pathway in HCC immune evasion, potentially paving the way for a new therapeutic approach for HCC. Coupled with observed upregulation of this signaling pathway in HCC patients treated with PD-1 therapy, it suggests that combining KRAS inhibitors with ICIs may be a viable clinical strategy to enhance immunotherapeutic efficacy.
Reference: Martina Mang Leng Lei, Terence Kin Wah Lee. Wild-Type Kirsten Rat Sarcoma (Kras) Promotes Immune Escape via Suppression of InterferonMediated Immunity in Hepatocellular Carcinoma. APPLE 2023 Abstract OP-07.
