Comprehensive analysis of SLC43A2 on the tumor immune microenvironment and prognosis of liver hepatocellular carcinoma

Abstract

Background: Tumor cells outcompete T cells for methionine via overexpressing SLC43A2, causing T cells exhaustion. We explored the influence of SLC43A2 on tumor immune microenvironment (TIME), immune-related genes (IRGs) and the prognosis of liver hepatocellular carcinoma (LIHC) patients. Methods:The TCGA-LIHC dataset (n = 374) and the ICGC-LIRI-JP-LIHC (n = 231) datasets were used as training and validation cohort, respectively. IRGs were obtained from ImmPort. Statistical analyses were performed using R (V 4.0.5). Online databases such as GEPIA, GSCALite, the Kaplan-Meier plotter, KEGG, TIMER2, and CMap were used for differential expression, immune infiltration, functional enrichment, survival, and drug-induced gene perturbation analysis.Results: SLC43A2 expression was higher in LIHC, correlated with worse survival, but could not predict prognosis of LIHC separately (AUC = 0.467). SLC43A2 positively correlated with immune exhaustion markers (all p < 0.001) and with increased infiltration of Tregs, macrophages and myeloid-derived suppressor cells (MDSC) (all p < 0.05). SLC43A2 may regulate 120 IRGs. A prognostic risk score model was developed using the TCGA-LIHC cohort and validated by the ICGC-LIRI-JP cohort. Arachidonic acid, SB-202190 and guanethidine were identified as possible immunomodulators pharmacologically targeting SLC43A2 in LIHC.Conclusion: SLC43A2 may create suppressive tumor microenvironment and regulate related IRGs, thus affecting the prognosis of LIHC. Arachidonic acid, SB-202190, and guanethidine may be worthy of further study as immunomodulators on SLC43A2.

Identification and Expression Analysis of Long Noncoding RNAs in Response to Infection with VHSV in Rainbow Trout

“…SLC43A2 is positively correlated with markers of immune exhaustion. SLC43A2 may contribute to the development of a suppressive tumor microenvironment and regulate immune-related genes, thereby influencing the prognosis of liver hepatocellular carcinoma [50]. This gene trans-acted with the MSTRG.982 as well.…”

Harnessing CD8+ T cell dynamics in hepatitis B virus‐associated liver diseases: Insights, therapies and future directions

“… 185 Additionally, solute carrier family 43 member 2 (SLC43A2), a methionine transporter, is associated with higher levels of CD8 + T cells, higher markers of T cell exhaustion and lower levels of naive CD8 + T cells, suggesting that SLC43A2 may regulate immune‐related genes, leading to CD8 + T cell exhaustion and impacting the TME and prognosis of HCC. 186 Therefore, supplementation of methionine and inhibition of tumour SLC43A2 can normalise methionine metabolism in effector T cells and restore their function, enhancing anti‐tumour immunity in preclinical models. 185 The supplementation of methionine additionally reduced the growth rate of HCC cells and induced the adenosine monophosphate‐activated protein kinase (AMPK) and mTOR pathways.…”

“…This disruption causes a decrease in H3K79me2 (an active transcriptional histone mark) and defects in the STAT5 signalling pathway in CD8 + T cells, impairing their immune function 185 . Additionally, solute carrier family 43 member 2 (SLC43A2), a methionine transporter, is associated with higher levels of CD8 + T cells, higher markers of T cell exhaustion and lower levels of naive CD8 + T cells, suggesting that SLC43A2 may regulate immune‐related genes, leading to CD8 + T cell exhaustion and impacting the TME and prognosis of HCC 186 . Therefore, supplementation of methionine and inhibition of tumour SLC43A2 can normalise methionine metabolism in effector T cells and restore their function, enhancing anti‐tumour immunity in preclinical models 185 .…”