Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack

by Selleckchem | Sep 26 2023

Background and aims: Monocarboxylate transporter (MCT) 4 is a high-affinity lactate transporter that is primarily involved in the maintenance of intracellular pH homeostasis and highly expressed in different tumors. However, the role of MCT4 in modulating immune responses against HCC remains unknown.

Approach and results: In this study, we demonstrated that MCT4 was overexpressed in HCC, which was associated with poor prognosis in patients. Genetic or pharmacological inhibition of MCT4 using VB124 (a highly potent MCT4 inhibitor) suppressed HCC tumor growth in immunocompetent mice model by enhancing CD8 + T cell infiltration and cytotoxicity. Such improved immunotherapy response by MCT4 targeting was due to combined consequences characterized by the alleviated acidification of tumor microenvironment and elevated the chemokine (C-X-C motif) ligand (CXCL) 9/CXCL10 secretion induced by reactive oxygen species/NF-κB signaling pathway. Combining MCT4 inhibition improved the therapeutic benefit of anti-programmed cell death 1 immunotherapy in HCC and prolonged mice survival. Moreover, higher MCT4 expression was observed in tumor tissues from nonresponder patients with HCC receiving neoadjuvant therapy with toripalimab.

Conclusions: Our results revealed that lactate exportation by MCT4 has a tumor-intrinsic function in generating an immunosuppressive HCC environment and demonstrated the proof of the concept of targeting MCT4 in tailoring HCC immunotherapeutic approaches.

Comments:

The study described aimed to investigate the role of Monocarboxylate transporter 4 (MCT4) in modulating immune responses against hepatocellular carcinoma (HCC), a type of liver cancer. The researchers found that MCT4 was overexpressed in HCC and was associated with a poor prognosis in patients.

To understand the impact of MCT4 on HCC, the researchers used genetic or pharmacological inhibition of MCT4 using a potent inhibitor called VB124. They observed that inhibiting MCT4 suppressed HCC tumor growth in mice models with intact immune systems. The inhibition of MCT4 led to enhanced infiltration and cytotoxicity of CD8+ T cells, a type of immune cell involved in fighting cancer.

The improved immunotherapy response observed after MCT4 targeting was attributed to multiple factors. First, inhibiting MCT4 reduced the acidification of the tumor microenvironment, which is known to be immunosuppressive. Additionally, MCT4 inhibition increased the secretion of chemokines (CXCL9 and CXCL10) that attract immune cells to the tumor site. This effect was mediated through the reactive oxygen species/NF-κB signaling pathway.

The researchers further investigated the combination of MCT4 inhibition with anti-programmed cell death 1 (anti-PD-1) immunotherapy, a type of cancer treatment that enhances the immune response against tumors. They found that combining MCT4 inhibition with anti-PD-1 therapy improved the therapeutic benefits and prolonged the survival of mice with HCC.

Finally, the study examined MCT4 expression in tumor tissues from HCC patients who received neoadjuvant therapy with toripalimab, a type of immune checkpoint inhibitor. They observed higher MCT4 expression in tumor tissues from nonresponsive patients, suggesting that MCT4 may be involved in resistance to immunotherapy in HCC.

In conclusion, the study demonstrated that MCT4 plays a crucial role in creating an immunosuppressive environment in HCC by exporting lactate. Targeting MCT4 showed potential in enhancing immunotherapy response and could be a promising strategy for tailoring HCC immunotherapeutic approaches.