Journal
FRONTIERS IN ONCOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2022.960066
Keywords
hepatocellular carcinoma; monocarboxylate transporter; lactate; regulatory T cells; treatment resistance
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Funding
- National Natural Science Foundation of China [81971504]
- Natural Science Foundation of Jiangsu [BK20201486]
- Post-Doctoral Special Foundation of China [2020M670065ZX]
- Post-Doctoral Foundation of Jiangsu Province [2020Z021]
- Medical and Health Science and Technology Program of Zhejiang Province [2021KY1036]
- Changzhou Society Development Funding [CE20205038]
- lifting Project of 2021 Young Scientific and Technological Talents in Changzhou
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Resistance to anti-PD-1 therapy in hepatocellular carcinoma (HCC) may be associated with monocarboxylate transporter (MCT) and lactate signaling in regulatory T cells (Tregs).
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.
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