The Golgi apparatus plays a critical role in the modification, sorting, and packaging of proteins for their eventual destinations, whether inside or outside the cell.
While fundamental, this function has seldom been scrutinized in the realm of cancer immunology, especially in comparison to organelles like the mitochondria or endoplasmic reticulum.
“Our curiosity centered around the Golgi apparatus; it’s a vital organelle. We sought to discover its transformation and role in T-cells regarding cancer combat,” stated Nathaniel Oberholtzer, an M.D./Ph.D. candidate in the lab of Shikhar Mehrotra at MUSC Hollings Cancer Center, who is also the scientific head of the Center for Cellular Therapy.
The findings suggest that the efficient functioning of the Golgi apparatus is crucial for T-cells to effectively target and destroy cancer cells. Insights into a signaling axis that alleviates Golgi stress, enabling optimal performance, could present novel therapeutic avenues to boost T-cell efficacy. Moreover, Oberholtzer’s research suggests that the Golgi could serve as a biomarker for selecting potent T-cells for immunotherapy.
Author Oberholtzer and senior author Mehrotra, with their Hollings cohort, have unveiled these findings in Science Advances.
T-cells are essential components of the immune system with the potential to annihilate cancer cells. CAR-T cells are lab-engineered derivatives that specifically target patient-specific cancer cell proteins.
Yet, both T-cells and CAR-T cells may exhibit “exhaustion” when in the unfavorable tumor environment. Mehrotra’s team investigates strategies to invigorate these cells, extending their cancer-fighting duration.
“The tumor milieu is advantageous to the tumor but adverse for incoming cells,” noted Mehrotra.
Similar to humans, cells endure ongoing stress, be it biochemical imbalances or mechanical strain. Temporary stress might benefit by fortifying the cells.
“Persistent stress, akin to the tumor environment, however, shifts the cellular state, eventually leading to deterioration,” Mehrotra explained.
Intriguingly, they found hydrogen sulfide treatment of the Golgi apparatus rendered T-cells more resilient to stress.
“Hydrogen sulfide, a gaseous signaling element present across mammalian cells, often a cellular byproduct, exhibits vital signaling responsibilities,” Oberholtzer stated.
“Proteins, through sulfhydration, where cysteine residues are modified, undergo activity alterations.”
Oberholtzer discovered this sulfhydration shields the Golgi apparatus from oxidative harm by modifying a protein named Prdx4.
“Under tumor-induced stress, Golgi disruption in T-cells occurs. Hydrogen sulfide mitigates this disruption,” Oberholtzer revealed.
Exploration into this protection led the team to scrutinize the Golgi apparatus further.
“Using the Golgi as a straightforward indicator, T-cells abundant in Golgi demonstrate robust tumor-killing capabilities,” noted Oberholtzer.
Employing flow cytometry at Hollings, T-cells were categorized based on their Golgi content into Golgi-hi and Golgi-lo.
“High-Golgi cells exhibit a distinct phenotype with reduced exhaustion and enhanced tumor control,” Mehrotra remarked.
This preliminary work posits that isolating Golgi-hi T-cells for patient reinfusion might enhance tumor control.
“We’re currently validating the potential for clinical trials at the Center for Cellular Therapy,” Oberholtzer shared.
Further studies will delve into the impact of Golgi stress amidst overall cellular organelle stress induced by the tumor environment.