Inactivating LATS2 variation drives tumor progression and resistance to anti-PD-1 therapy in intrahepatic...

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• Recurrence significantly limits long-term survival in intrahepatic cholangiocarcinoma (ICC) patients.
• Molecular drivers and therapeutic targets for ICC remain largely undefined, necessitating further research.

Purpose of the Study:

• To investigate the role of LATS2 gene variations in ICC.
• To determine the impact of LATS2 alterations on patient survival and response to anti-PD-1 therapy.
• To elucidate the underlying mechanisms of LATS2 in ICC progression and immune evasion.

Main Methods:

• Targeted and Sanger sequencing, and quantitative PCR were used to analyze LATS2 in 400 ICC samples.
• Kaplan-Meier survival analysis assessed the impact of LATS2 mutations and copy number loss on patient outcomes.
• Functional studies explored LATS2's role in the Hippo signaling pathway, immune evasion, and anti-PD-1 therapy resistance.

Main Results:

• LATS2 somatic mutations (3%) and copy number loss (34%) were identified in ICC, both correlating with decreased LATS2 expression, increased recurrence, and poorer survival.
• LATS2 inactivation suppressed the Hippo pathway, leading to YAP activation, PD-L1 upregulation, and CCL2 secretion.
• Tumor immune evasion was promoted through suppressed CD8+ T cell infiltration and increased M2-like macrophage recruitment, contributing to anti-PD-1 resistance.

Conclusions:

• LATS2-inactivating variations are clinically associated with ICC progression and poor survival.
• LATS2 alterations represent a potential biomarker for guiding precision therapy in ICC patients.
• Understanding LATS2's mechanistic role offers insights into overcoming immune evasion and therapeutic resistance in ICC.