Inactivating LATS2 Variation Drives Tumor Progression and Resistance to Anti-PD-1 Therapy in Intrahepatic Cholangiocarcinoma

Background /Aims: Recurrence is a major factor limiting the long-term survival of patients with intrahepatic cholangiocarcinoma (ICC). The molecular characteristics and potential therapeutic targets in ICC remain largely undefined. Methods: Following our previous whole-exome sequencing study, we performed targeted sequencing, Sanger sequencing, and quantitative PCR to assess all coding exons and copy number variations of LATS2 in 400 primary ICC samples. Kaplan-Meier survival curves were used to assess the impact of LATS2 mutation, copy number loss, and low expression levels on recurrence-free survival and overall survival in ICC patients. In addition, we investigated the functional role and underlying mechanisms of LATS2 variation in ICC tumor progression and resistance to anti-PD1 therapy. Results: Among a total of 400 ICC cases, the overall frequencies of LATS2 somatic mutation and copy number loss were 3% (12/400) and 34% (136/400), respectively. Both types of variation were correlated with decreased LATS2 protein expression, increased tumor recurrence, and poor overall survival. Biofunctional investigations revealed a tumor-suppressor role of LATS2. Inactivation of LATS2 suppressed the Hippo signaling pathway, leading to aberrant activation of YAP, which upregulated PD-L1 expression and CCL2 secretion, suppressed CD8+ T cell infiltration, and enhanced recruitment of M2-like macrophages, thereby promoting immune evasion, tumor progression, and resistance to anti-PD-1 therapy. Conclusions: Our study reveals a pivotal clinical association and mechanistic role of LATS2-inactivating variation in ICC, which may serve as a useful biomarker for precision therapy.