IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction

Area of Science:

• Immunology
• Oncology
• Hepatology

Background:

• Natural killer (NK) cells possess significant antitumor capabilities.
• A substantial population of NK cells in the human liver are tissue-resident.
• The antitumor functions of liver-resident versus infiltrating NK cells in liver tumors remain uninvestigated.

Purpose of the Study:

• To investigate the characteristics and antitumor functions of liver-resident and liver-infiltrating NK cells within human liver tumors.
• To compare NK cell populations in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) liver metastases with unaffected liver tissue.
• To explore mechanisms of NK cell dysfunction in the tumor microenvironment and potential therapeutic interventions.

Main Methods:

• Ex vivo analysis of NK cells from human HCC and liver CRC metastases and matched normal liver tissue.
• Phenotypic characterization using markers like CXCR6, CD69, and NKG2D.
• Assessment of NK cell proliferation (Ki67), cytotoxicity, and cytokine production.
• In vitro coculture experiments with hepatoma cell lines and autologous tumor cells.
• Interleukin-15 (IL-15) treatment to evaluate functional recovery.

Main Results:

• NK cells were prevalent in liver tumors but at lower frequencies than in normal liver.
• A high proportion (up to 79%) of intratumoral NK cells exhibited a liver-resident phenotype (CXCR6+CD69+).
• Liver-resident NK cells showed higher NKG2D expression ex vivo, but NKG2D was downregulated in tumor-infiltrating NK cells.
• Intratumoral NK cells displayed impaired cytotoxicity and reduced cytokine production, linked to NKG2D downregulation and impaired proliferation.
• Cell contact with tumor cells induced NK cell inhibition, which could be reversed by IL-15 treatment.

Conclusions:

• Impaired NK cell antitumor function in liver tumors results from intrinsic tolerogenic properties of liver-resident NK cells and contact-dependent inhibition by HCC.
• NKG2D downregulation and impaired proliferation contribute to NK cell dysfunction within the tumor microenvironment.
• IL-15 demonstrates potential as a therapeutic agent to restore hepatic NK cell antitumor activity in cancer immunotherapy.