Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma

Abstract

IntroductionGlioblastoma is a malignant brain tumor with poor prognosis. Lactate is the main product of tumor cells, and its secretion may relate to immunocytes’ activation. However, its role in glioblastoma is poorly understood. MethodsThis work performed bulk RNA-seq analysis and single cell RNA-seq analysis to explore the role of lactate in glioblastoma progression. Over 1400 glioblastoma samples were grouped into different clusters according to their expression and the results were validated with our own data, the xiangya cohort. Immunocytes infiltration analysis, immunogram and the map of immune checkpoint genes’ expression were applied to analyze the potential connection between the lactate level with tumor immune microenvironment. Furthermore, machine learning algorithms and cell-cell interaction algorithm were introduced to reveal the connection of tumor cells with immunocytes. By co-culturing CD8 T cells with tumor cells, and performing immunohistochemistry on Xiangya cohort samples further validated results from previous analysis.DiscussionIn this work, lactate is proved that contributes to glioblastoma immune suppressive microenvironment. High level of lactate in tumor microenvironment can affect CD8 T cells’ migration and infiltration ratio in glioblastoma. To step further, potential compounds that targets to samples from different groups were also predicted for future exploration.

Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity

“…The unhindered formation of the immunosuppressive microenvironment is attributed in part to the paradoxical action of lactate in inhibiting CD8+ Teff migration while supporting CD4+ Treg survival. 129 Considering the scRNA‐seq data, we reproduced and examined a heterogeneous group of Foxp3+ NKTregs that express high levels of CD4, CD25R, Foxp3, programmed cell death1 (PDCD1), CTLA‐4, inducible co‐stimulator(ICOS) and T cell immunoreceptor with Ig and ITIM domains(TIGIT), among others, and acquired a phenotype very similar to that of inhibitory CD4+ Tregs in depth; these cells proactively exploit favourable conditions, efficiently convert lactate to pyruvate, and subsequently enter the mitochondrial TCA cycle. 130 Furthermore, Tregs actively absorb lactate by triggering monocarboxylate transporter 1 (MCT1) to indirectly limit PD‐1 expression on Teffs.…”

Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment

“…These metabolites regulate transcriptional responses and modulate the expression of target genes via transactivation or transrepression domains (Angelin et al 2017 ; Feng et al 2017 ; Kuang et al 2017 ; Walton et al 2018 ). Furthermore, the metabolic reprogramming of tumor-infiltrating cells leads to differentiation and acquisition of effector functions (Stone et al 2019 ; Wang H et al 2020 ; Han et al 2023 ; Wang Z et al 2023 ).…”