Journal Article

Inhibition of CMTM4 Sensitizes Cholangiocarcinoma and Hepatocellular Carcinoma to T Cell–Mediated Antitumor Immunity Through PD‐L1

Goh, Chi‐Ching, Wong, Carmen Chak‐Lui, Zhang, Misty Shuo, Cheu, Jacinth Wing‐Sum, Ng, Irene Oi‐Lin, Lee, Derek, Chiu, David Kung‐Chun, Chui, Noreen Nog‐Qin, Yuen, Vincent Wai‐Hin

2022

Overview

Liver cancers consist primarily of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors have emerged as promising therapeutic agents against liver cancers. Programmed cell death protein 1 (PD‐1) is an immunoinhibitory receptor present on T cells that interacts with its ligand programmed death‐ligand 1 (PD‐L1) found on cancer cells. Blocking PD‐1/PD‐L1 binding improves T‐cell survival, proliferation and cytotoxicity, which enhances their antitumor activity. Better understanding of the molecular mechanisms governing PD‐1/PD‐L1 response is essential to the development of predictive markers and therapeutic combinations that could improve the efficiency of anti‐PD‐1/PD‐L1 treatment. Chemokine‐like factor (CKLF)–like MARVEL transmembrane domain–containing 6 (CMTM6) has been recently identified as a major regulator of PD‐L1. Another member in the CMTM family, CKLF‐like MARVEL transmembrane domain–containing 4 (CMTM4), has been shown to compensate for the effects of CMTM6 when CMTM6 is lost. Interestingly, we found that CMTM4 is the major regulator of PD‐L1 in the context of liver cancer. Up‐regulated CMTM4 in patients with HCC and ICC is associated with poor patient survival, potentially due to its function in stabilizing PD‐L1 expression, hence facilitating escape from T cell–mediated cytotoxicity. We confirmed the role of CMTM4 as a positive regulator of PD‐L1 in multiple HCC and ICC cell lines and demonstrated that CMTM4 stabilizes PD‐L1 through posttranslational mechanisms. In vivo, suppression of Cmtm4 inhibited HCC growth and increased CD8+ T‐cell infiltration in immunocompetent mice. Furthermore, we found that depletion of CMTM4 sensitized HCC tumor to anti‐PD‐L1 treatment compared with control. This suggests that CMTM4 expression level could be a predictive marker for patient response to anti‐PD‐L1 treatment, and CMTM4 depletion can potentially be used to enhance the clinical benefits of anti‐PD‐L1 immunotherapy in patients with liver cancer. CMTM4 stabilizes PD‐L1 on liver cancer cells. CMTM4‐low ICC/HCC, which expresses lower PD‐L1, could be completely blocked by anti‐PD‐L1 mAb.

• Publisher: Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins,John Wiley and Sons Inc,Wolters Kluwer Health/LWW
• Subject: Animals / Antigens / Apoptosis / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - immunology / Carcinoma, Hepatocellular - metabolism / Cells, Cultured / Cholangiocarcinoma / Cholangiocarcinoma - drug therapy / Cholangiocarcinoma - immunology / Cholangiocarcinoma - metabolism / CRISPR / Cytotoxicity / Experiments / Growth factors / Hepatocytes / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - therapeutic use / Immunotherapy / Kinases / Ligands / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - immunology / Liver Neoplasms - metabolism / Lymphocytes / MARVEL Domain-Containing Proteins - antagonists & inhibitors / MARVEL Domain-Containing Proteins - genetics / Medical prognosis / Medical research / Mice / Mice, Inbred C57BL / Original / Plasmids / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - immunology / Proteins / Tumors / Up-Regulation / Veins & arteries