Tescalcin is a phagocytic checkpoint driving immune escape and limiting immunotherapeutic efficacy in hepatocellular carcinoma
Jiong-Liang Wang, Jun-Cheng Wang, Yangxun Pan, Minrui He, Zhikai Zheng, Hao Zou, Tianqing Wu, Yuhan Zhang, Zili Hu, Yizhen Fu, Wei Peng, Zhenyun Yang, Li Xu, Yao-Jun Zhang, Min-Shan Chen, Dandan Hu, Jinbin Chen, Ming Zhao, Dong-Ping Chen, Zhong-Guo Zhou
Jiong-Liang Wang, Jun-Cheng Wang, Yangxun Pan, Minrui He, Zhikai Zheng, Hao Zou, Tianqing Wu, Yuhan Zhang, Zili Hu, Yizhen Fu, Wei Peng, Zhenyun Yang, Li Xu, Yao-Jun Zhang, Min-Shan Chen, Dandan Hu, Jinbin Chen, Ming Zhao, Dong-Ping Chen, Zhong-Guo Zhou
View: Text | PDF
Research In-Press Preview Hepatology Immunology Oncology

Tescalcin is a phagocytic checkpoint driving immune escape and limiting immunotherapeutic efficacy in hepatocellular carcinoma

Abstract

Immunotherapies achieve durable responses in several cancers but show limited efficacy in refractory hepatocellular carcinoma (HCC). The mechanisms by which hepatoma cells evade immune recognition and limit immune checkpoint blockade (ICB) efficacy are incompletely defined. Here, we identified tumor-intrinsic tescalcin (TESC) as a previously unrecognized phagocytic checkpoint that contributes to immune evasion and ICB resistance in HCC. Mechanistically, H3K4 methylation drove TESC expression in hepatoma cells, facilitating cytosolic Ca²⁺ buffering and attenuating endoplasmic reticulum (ER) stress-induced calreticulin (CALR) plasma membrane exposure, an essential “eat-me” signal. Consequently, this process abrogates membrane CALR-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells, thereby impairing antigen presentation and subsequent T-cell activation. Clinically, elevated H3K4me3-TESC signaling was a promising prognostic biomarker for poor ICB response of HCC. Importantly, in vivo disruption of this axis restored APC phagocytic function and enhanced the antitumor effects of ICB therapy. Thus, targeting TESC-driven immune escape and its underlying epigenetic regulation may restore APC function and offer a precise therapeutic strategy to enhance immunotherapy efficacy in HCC.

Authors

Jiong-Liang Wang, Jun-Cheng Wang, Yangxun Pan, Minrui He, Zhikai Zheng, Hao Zou, Tianqing Wu, Yuhan Zhang, Zili Hu, Yizhen Fu, Wei Peng, Zhenyun Yang, Li Xu, Yao-Jun Zhang, Min-Shan Chen, Dandan Hu, Jinbin Chen, Ming Zhao, Dong-Ping Chen, Zhong-Guo Zhou

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

Unedited blot and gel images - Download (1.49 MB)

Advertisement