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LATS1/2 loss promote tumor immune evasion in endometrial cancer through downregulating MHC-I expression
Qianlan Yang1,2, Zehen Lv3,2, Mengfei Wang1,2
1Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Background:
LATS1/2 are frequently mutated and down-regulated in endometrial cancer (EC), but the contributions of LATS1/2 in EC progression remains unclear. Impaired antigen presentation due to mutations or downregulation of the major histocompatibility complex class I (MHC-I) has been implicated in tumor immune evasion. Herein, we elucidate the oncogenic role that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I.
Methods:
The mutation and expression as well as the clinical significance of LATS1/2 in EC was assessed in the TCGA cohort and our sample cohort. CRISPR-Cas9 was used to construct knockout cell lines of LATS1/2 in EC. Differentially expressed genes were analyzed by RNA-seq. The interaction between LATS1/2 and STAT1 was verified using co-immunoprecipitation and GST pull-down assays. Mass spectrometry, in vitro kinase assays, ChIP-qPCR, flow cytometry, immunohistochemistry, immunofluorescence and confocal microscopy were performed to investigate the regulation of LATS1/2 on MHC-I through interaction with and phosphorylate STAT1. The killing effect of activated PBMCs on EC cells were used to monitor anti-tumor activity.
Results:
Here, we demonstrate that LATS1/2 are frequently mutated and down-regulated in EC. Moreover, LATS1/2 loss was found to be associated with a significant down-regulation of MHC-I, independently of the Hippo-YAP pathway. Instead, LATS1/2 were found to directly interact with and phosphorylate STAT1 at Ser727, a crucial transcription factor for MHC-I upregulation in response to interferon-gamma (IFN-γ) signaling, to promote STAT1 accumulating and moving into the nucleus to enhance the transcriptional activation of IRF1/NLRC5 on MHC-I. Additionally, the loss of LATS1/2 was observed to confer increased resistance of EC cells to immune cell-mediated killing and this resistance could be reversed by over-expression of MHC-I.
Conclusion:
Our findings indicate that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I, leading to the suppression of infiltrating activated CD8 + T cells and highlight the importance of LATS1/2 in IFN-γ signaling-mediated tumor immune response, suggesting that LATS1/2 is a promising target for immune checkpoint blockade therapy in EC.
Insights
Large tumor suppressor kinase 1/2 (LATS1/2) loss in endometrial cancer (EC) promotes immune evasion by downregulating major histocompatibility complex class I (MHC-I). Restoring MHC-I expression can reverse EC cells' resistance to anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Large tumor suppressor kinase 1/2 (LATS1/2) are frequently mutated and downregulated in endometrial cancer (EC).
- Impaired antigen presentation via major histocompatibility complex class I (MHC-I) downregulation contributes to tumor immune evasion.
- The precise role of LATS1/2 dysregulation in EC immune evasion remains unclear.
Purpose of the Study:
- To elucidate the oncogenic role of LATS1/2 dysregulation in EC.
- To investigate the mechanism by which LATS1/2 impacts immune evasion through MHC-I regulation.
- To explore LATS1/2 as a potential therapeutic target for EC immunotherapy.
Main Methods:
- Analysis of LATS1/2 mutation, expression, and clinical significance in EC patient cohorts (TCGA and local).
- Construction of LATS1/2 knockout EC cell lines using CRISPR-Cas9.
- RNA-sequencing for differential gene expression analysis.
- Co-immunoprecipitation and GST pull-down assays to confirm LATS1/2-STAT1 interaction.
- Mass spectrometry, kinase assays, ChIP-qPCR, flow cytometry, and immunohistochemistry to investigate LATS1/2 regulation of MHC-I via STAT1 phosphorylation.
- Assessment of anti-tumor activity using peripheral blood mononuclear cell (PBMC) killing assays.
Main Results:
- LATS1/2 are frequently mutated and downregulated in EC, correlating with decreased MHC-I expression independently of the Hippo-YAP pathway.
- LATS1/2 directly interact with and phosphorylate STAT1 at Ser727, enhancing its nuclear accumulation and promoting IRF1/NLRC5-mediated MHC-I transcription.
- Loss of LATS1/2 confers resistance to immune cell-mediated killing, which is reversible by MHC-I re-expression.
Conclusions:
- LATS1/2 downregulation in EC leads to immune evasion via decreased MHC-I expression, suppressing CD8+ T cell infiltration.
- LATS1/2 play a critical role in interferon-gamma (IFN-γ) signaling-mediated anti-tumor immune responses.
- LATS1/2 represent a promising therapeutic target for immune checkpoint blockade therapy in EC.
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