Lipids for CD8+ TILs: Beneficial or harmful?

Abstract

Lipids and lipid metabolism play crucial roles in regulating T cell function and are tightly related to the establishment of immune memory. It is reported that tumor-infiltrating CD8⁺T lymphocytes (CD8⁺TILs) burn fats to restore their impaired effector function due to the lack of glucose. Conversely, fatty acids (FAs) and cholesterol in the tumor microenvironment (TME) drive the CD8⁺ TILs dysfunction. The origin of dysfunctional CD8⁺ TILs shares important features with memory T cell's precursor, but whether lipids and/or lipid metabolism reprogramming directly influence the memory plasticity of dysfunctional CD8⁺ TILs remains elusive. It is necessary to understand the interplay between cellular lipid metabolism and dysfunction of CD8⁺ TILs in the case of targeting T cell's metabolism to synergize cancer immunotherapy. Therefore, in this review, we summarize the latest research on CD8⁺ TILs lipid metabolism, evaluate the impacts of lipids in the TME to CD8⁺ TILs, and highlight the significance of promoting memory phenotype cell formation by targeting CD8⁺ T cells lipid metabolism to provide longer duration of cancer immunotherapy efficacy.

Keywords: CD8+ T cell; Exhausted T cell; cholesterol; fatty acid; fatty acid oxidation; metabolism; tumor microenvironment (TME).

Figure 1

TME lipids dictate CD8⁺ TILs functional heterogeneity. (A) CD8⁺ TILs utilize aerobic glycolysis to support their antitumor effects, which is inhibited in a glucose-deprived TME. Instead of relying on glucose, CD8 +TILs upregulate PPARα-mediated CPT1A expression in response to the environmental FAs and the FAO is therefore increased to compensate the energy deficit. This compensatory circuit is further reinforced by PD-1 signaling due to its inhibitory effects on aerobic glycolysis. (B) Increased uptake of TME FAs and oxidized lipids by CD36 drive CD8⁺ TILs dysfunction. Both Arachnoid acid (AA) and oxidized low density lipoprotein (ox-LDL) induce abnormal cell death by ferroptosis, ox-LDL also increases p38 phosphorylation, which inhibits the transcription of effector cytokines like TNFα and IFNγ. LCFAs and VLCFAs poison CD8⁺ TILs through lipotoxicity and inhibit the VLCAD expression that in turn accelerates the accumulation of LCFAs and VLCFAs. (C) Tc9 cells are resistant to lipid peroxidation and ferroptosis by its IL-9 autocrine-mediated STAT3/FAO pathway, which is impaired in the cholesterol-enriched TME. Oxysterol promotes the sumoylation of LXR that inhibits the p65 binding on IL-9 promoter and therefore decreased expression. Moreover, cholesterol accumulation in the cytoplasm promote ER stress sensor (XBP1) expression to directly induce inhibitory receptor expressions including PD-1 and 2B4.

Figure 2

Developmental trajectories of Tex cells. The TCF1⁺Tim-3^- progenitor Tex cells denote a cluster of Tex cells with self-renew ability that differentiate into TCF1^-Tim-3⁺ Terminal Tex cells when responding to ICIs, such as PD-1 inhibitors. TCF1 and newly identified OCT2 are signature molecules for the progenitor Tex cells memory-like plasticity. They emerge and develop from either GZMK⁺ Tem cells or ZNF683⁺CXCR6⁺ Trm cells in the chronic antigenic stimulation circumstance and share memory-like features with TCF1⁺CXCR5⁺CD127^high MPECs that give rise to Tmem cells after the antigen clearance. The TCF1^-Tim-3⁺ terminal Tex cells lose lipid metabolic plasticity along with the downregulation of GPX4. Though they derive a fraction of recovering Tex cells reacquiring TCF1 and CD127 expressions after chronic antigen elimination, the PD-1^highKLRG1^low Teff cells generated from the recovering Tex cells can’t efficiently eliminate a secondary antigen challenge because of the defect polyfunctionality.