A T cell resilience model associated with response to immunotherapy in multiple tumor types

Lipids for CD8+ TILs: Beneficial or harmful?

“…One recently published article identified genetic ablation of Fibp led to better survival and superior antitumor effector function of human and mice CD8 + TILs in high cholesterol TME. Fibp knockout CD8 + TILs reduced extracellular cholesterol uptake, downregulated cholesterol biosynthetic enzymes, and rendered lower cellular cholesterol levels compared to control counterparts, which was independent of extracellular cholesterol doses (45). By contrast, in an earlier study, researchers found that restricting CD8 + T cells' cholesterol esterification was beneficial for their antitumor function.…”

“…However, according to the most recent study, it is unfavorable to directly target CD8 + T cells' cholesterol biosynthesis by statins. Statins elevated the cellular cholesterol levels in activated CD8 + T cells and inhibited their proliferation (45). Intriguingly, in an earlier study, simvastatin, a lipophilic statin, was found to not only act as a cancer vaccine adjuvant but also synergize anti PD-1 therapy in multiple animal models through decreasing the geranylgeranylation of small GTPases and regulating endosomal trafficking in dendritic cells which led to better antigen presentations (41) (Table 2).…”

“…Like FAs, the roles of cholesterol in T cell functions are controversial. Lowering cellular cholesterol level helps restore CD8 TILs effector function (12,21,45), while that may inhibit TCR signaling at the early phase of CD8 T cells activation (16,17). Within cholesterol-enriched TME, cellular cholesterol positively correlates with the PD-1, 2B4, LAG-3, and Tim3 expression on CD8 + TILs.…”

“…Intriguingly, in an earlier study, simvastatin, a lipophilic statin, was found to not only act as a cancer vaccine adjuvant but also synergize anti PD-1 therapy in multiple animal models through decreasing the geranylgeranylation of small GTPases and regulating endosomal trafficking in dendritic cells which led to better antigen presentations (41) (Table 2). Opposite to directly targeting the cholesterol biosynthetic enzyme, genetically targeting Fibp generated favorable cellular cholesterol-lowering effects in CD8 + T cells while remained their basal cholesterol biosynthesis (45). However, the biological effects of Fibp still remain largely unknown, and the beneficial effect in sustaining CD8 + T cells resilience in cholesterol enriched TME waits for further investigations to expand its potential clinical applications in cancer immunotherapy.…”

Big data in basic and translational cancer research

“…For example, the transcriptomic data atlas collected from cytokine treatments in bulk cell cultures has enabled the reliable inference of signalling activities in scRNA-seq data 34 . Further, single-cell signalling activities inferred through bulk data have been used to reveal therapeutic targets, such as FIBP , to potentiate cellular therapies in solid tumours and molecular programmes of T cells that are resilient to immunosuppression in cancer 54 . In another example, the analysis of more than 50,000 scRNA-seq profiles from 35 pancreatic adenocarcinomas and control samples revealed edge cells among non-neoplastic acinar cells, whose transcriptomes have drifted towards malignant pancreatic adenocarcinoma cells 55 ; TCGA bulk pancreatic adenocarcinoma data were then used to validate the edge-cell signatures inferred from the single-cell data.…”