Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients

Abstract

BackgroundProgrammed cell death-1 (PD-1) immune checkpoint inhibitors are not effective in treating all patients with hepatocellular carcinoma (HCC), and regulatory T cells (Tregs) may determine the resistance to anti-PD-1 therapy.MethodsPatients were divided into two groups based on the clinical efficacy of anti-PD-1 therapy. Flow cytometry was used to determine the phenotype of CD4+, CD8+, and Tregs in peripheral blood mononuclear cells (PBMCs). CD4+CD45RA+T cells were sorted to analyze Treg differentiation and function.ResultsNo significant differences were found between resistant and sensitive patients in the percentage of CD4+ T cells and Tregs in PBMCs or the differentiation and function of induced Tregs (iTregs). However, iTregs from resistant patients presented higher monocarboxylate transporter (MCT) expression. Lactate induced more iTregs and improved OXPHOS levels in the resistant group. MCT1 and MCT2 were highly expressed in tumor-infiltrating Tregs, and patients with higher MCT1 expression had worse clinical outcomes. Combinatorial therapy with MCT antibody and anti-PD-1 therapy effectively inhibited tumor growth.ConclusionMCT and its downstream lactate signal in Tregs can confer anti-PD-1 resistance and may be a marker of poor prognosis in HCC.

Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8 + T cell memory development

“…Recently, MCT1 was shown to be responsible for lactate intake and oxidation by Tregs in low-glucose/high-lactate environment such as solid tumors ( 23 , 24 ). Moreover, MCT1 and downstream lactate signaling in Tregs can confer resistance to anti-PD1 therapy and would be a marker of poor prognosis in hepatocellular carcinoma ( 57 ). Initial experimental studies, however, described MCT1 as an indispensable transporter for the extraction of lactate from human activated T lymphocytes, pharmacological inhibition of MCT1 activity limiting cell proliferation ( 22 ).…”

Research progress of abnormal lactate metabolism and lactate modification in immunotherapy of hepatocellular carcinoma

“…In lactate-mediated TME, PD-1 is more expressed in Tregs than in effector T cells. MCT1 upregulation in Tregs and its downstream lactate signaling promote resistance to anti-PD-1 therapy in HCC patients (244). MCT1 inhibitor AZD3965 was combined with anti-ICIs to enhance the immunity of antigenspecific CD8 T cells to tumors, effectively inhibiting tumor growth (220).…”

Proton-coupled monocarboxylate transporters in cancer: From metabolic crosstalk, immunosuppression and anti-apoptosis to clinical applications

“…PD- 1 blockade activates PD- 1-expressing Treg cells and inhibits effector T cells, including CD8 + T cells, which play a crucial role in killing cancer cells in the host, ultimately leading to treatment failure ( Wherry and Kurachi, 2015 ). Combined treatment with MCT antibody and anti-PD- 1 can effectively inhibit tumor growth ( Zhou et al, 2022 ).…”