The ER-Mitochondria Interface as a Dynamic Hub for T Cell Efficacy in Solid Tumors

Abstract

The endoplasmic reticulum (ER) is a large continuous membranous organelle that plays a central role as the hub of protein and lipid synthesis while the mitochondria is the principal location for energy production. T cells are an immune subset exhibiting robust dependence on ER and mitochondrial function based on the need for protein synthesis and secretion and metabolic dexterity associated with foreign antigen recognition and cytotoxic effector response. Intimate connections exist at mitochondrial-ER contact sites (MERCs) that serve as the structural and biochemical platforms for cellular metabolic homeostasis through regulation of fission and fusion as well as glucose, Ca2+, and lipid exchange. Work in the tumor immunotherapy field indicates that the complex interplay of nutrient deprivation and tumor antigen stimulation in the tumor microenvironment places stress on the ER and mitochondria, causing dysfunction in organellar structure and loss of metabolic homeostasis. Here, we assess prior literature that establishes how the structural interface of these two organelles is impacted by the stress of solid tumors along with recent advances in the manipulation of organelle homeostasis at MERCs in T cells. These findings provide strong evidence for increased tumor immunity using unique therapeutic avenues that recharge cellular metabolic homeostasis in T cells.

ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection

“…Multiple lines of evidence link chronic ER stress to mitochondrial fission and increased mitochondrial-ER contacts. 75 , 113 Although we did not identify protein expression differences in the mitochondrial morphology regulators phospho/total Drp1, or Opa1, intriguingly we did note an increase in MERCS formation in the setting of Sel1L loss. ER tubules have been shown to mediate mitochondrial fission through physical constriction of mitochondrial membranes, 114 raising an intriguing possibility of whether increased MERCS formation is responsible for the mitochondrial fission noted.…”

“…Mitochondrial fusion and fission is a tightly regulated process in association with mitochondrial-ER contact sites (MERCS). 75 , 76 There was no difference in expression of the mitochondrial morphology regulators Drp1 and Opa1 ( Figure S6B ), 74 , 77 , 78 so we investigated MERCS formation. Super-resolution microscopy for ER (KDEL) and mitochondria (TOM20) of WT and Se1lLcKO T ACT cells revealed an increase in ER-associated mitochondria ( Figure S6C ), consistent with increased MERCS formation in the absence of Sel1L.…”

“…However, MERCS also serve a wide variety of other cellular functions, including calcium homeostasis and lipid exchange. 75 , 76 , 115 Mitochondrial-ER interplay has been increasingly recognized to play key roles in T cell fate and function. 115 – 117 Thus, additional work to define exactly how ERAD regulates MERCS formation and immunometabolic functions will be critical to understanding how ER homeostasis pathways regulate T cell metabolism.…”

Acetyl-CoA Carboxylase Obstructs CD8+T-Cell Lipid Utilization and Energy Synthesis in the Tumor Microenvironment

“…Finally, the organellar structural differences between vehicle and ACCi-conditioned T cells shed light on the importance ER-mitochondrial contacts previously identified to be enriched in memory T cells (Hunt et al ., 2022). It is striking that modulation of the activity of a singular enzyme can reshape both the complete cellular lipidome and organelle structure in T cells.…”

“…Bcl2, found at mitochondria-ER contact sites (MERCs), potentiates maintenance of mitochondria structural dynamics (Aouacheria et al, 2017; Hunt et al, 2022). Given that ACCi resulted in differential ER-mitochondria crosstalk evidenced by increased utilization of ER-derived lipid (Figure 5), we performed transmission electron microscopy (TEM) to visualize organelle structure between vehicle and ACCi T cell groups.…”