The human immune system has an arsenal of different tools to kill cancer cells, including T cells, neutrophils, and macrophages. Out of the trio, T cells are the most effective killing machines, capable of relentlessly hunting down aberrant cancer cells.
While macrophages and neutrophils can often self-destruct after ingesting cancer cells or pathogens, T cells tend to be more persistent. The downside to this is a vulnerability to fatigue, especially in aggressive tumor environments, due to relentless stress.
Exhaustion can render T cells markedly less effective at their job, giving cancer a chance to grow out of control. Finding ways to address fatigue in T cells is a priority for cancer researchers.
A recent study co-authored by Shikhar Mehrotra, Ph.D, and Nathaniel Oberholtzer MD, from the MUSC College of Medicine, hints at a role played by an important organelle that is often overlooked inside our cells – the Golgi apparatus.
A Cancerous Tumor is a Hostile Zone for Immune Cells
Mild to moderate levels of stress can be beneficial for T cells. It can have the same effect that adequate exercise has on the muscles in our body, improving their immune response and making them more effective at killing cancer cells.
However, the opposite is also true in the case of overexertion. While it can lead to fatigue, soreness, and tears in muscles, constant stress can cause exhaustion of T cells. In extreme cases, the cell can collapse and die.
A tumor microenvironment (TME) is designed to accommodate only cancer cells. Other healthy cells, including T cells that enter this zone, will be subjected to various types of stressors. They can include the following:
- Hypoxia: cancer cells consume vast amounts of oxygen, leaving TMEs with hypoxia (low oxygen levels). Hypoxic environments impair T cell function and can make them exhausted.
- Metabolic stress: tumors also reduce the levels of essential nutrients and amino acids available to immune cells, starving them and making them less effective in the long run.
- Immune suppression: TMEs often hijack various other healthy cells that are designed to suppress T cells (as part of a system of checks and balances). Overexpression of cells like Tregs and MDSCs can dampen the immune response.
Continuous activation and suppression inside such a hostile environment will eventually lead to the exhaustion of T cells. This can be further accelerated by the presence of metabolic byproducts like lactic acid.
The Hitherto Unknown Role of Golgi Bodies
Golgi bodies, also known as the Golgi apparatus, are important organelles inside our cells, alongside other organelles like the mitochondria, nucleus, lysosomes, and ribosomes. The function of this stacked and layered structure can be compared to that of an Amazon fulfillment center.
The packages handled, sorted, and dispatched by the Golgi apparatus can include all protein molecules manufactured by the cell. These molecules are “labeled” with sugars, phosphate groups, or lipids and sent out to various destinations both inside and outside the cell.
While their core functions have been extensively studied over the decades, we are still in the early stages of learning about the Golgi’s role in cancer immunology. According to the MUSC research team, the Golgi apparatus inside T cells is directly affected by fatigue levels of the host cells.
The Golgi apparatus inside exhausted T cells is rendered ineffective, fragmented, and diminished. They are also more prone to damage due to oxidative stress. In comparison, a healthy T cell will have a much larger, more visibly pronounced Golgi structure.
The Impact of Hydrogen Sulfide on Golgi Bodies
Hydrogen Sulfide (H2S) is a common by-product of various cellular processes inside the body. Several studies have already established its role as a potent signaling agent for immune cells. In certain autoimmune diseases like rheumatoid arthritis, lower volumes of H2S are often linked to flare-ups and poor immune response.
When the MUSC researchers looked at H2S levels of activated T cells inside a TME, they spotted signs of a marked decrease over time. Terminally exhausted T cells had very low H2S production levels. In stark contrast, when low doses of H2S were supplied to these cells, a raft of positive changes were noted:
- The T cells showed lower exhaustion levels and better immune function
- An increase in the levels of GM130 proteins that prevent Golgi fragmentation
- The Prdx4 enzyme stays inside the Golgi apparatus
The impact on Prdx4 is quite significant since it is an enzyme that helps reduce oxidative stress inside the Golgi apparatus. Prolonged stress can reduce its presence, increasing damage caused by oxidative stress.
Treating the T cells with H2S seems to help the Golgi apparatus to better avoid shrinkage and disintegration due to oxidative stress. Further, T cells with larger, more pronounced Golgi bodies displayed improved effectiveness at fighting cancer cells inside the TME.
The Key Takeaways of the MUSC Study for Cancer Immunotherapy
One of the approaches in immunotherapy involves taking T cells from the patient and genetically modifying them in a lab to make them more adept at binding to specific proteins on the cancer cells.
These T cells are called Chimeric Antigen Receptor T cells or CAR T cells. After modification, the CAR T cells are further cultured in the lab to increase their numbers and then injected back into the patient’s body.
The MUSC team also looked at the impact of H2S and Golgi apparatus on the performance of CAR T cells. The result was similar to regular T cells, with exhausted CAR T cells also having smaller, fragmented Golgi bodies.
This opens up some interesting possibilities. Isolating the CAR T cells with the largest Golgi bodies and injecting them into the patient should result in a stronger, more sustained anti-tumor action. It could give the patient a better chance of beating the disease.
The Center for Cellular Therapy at MUSC College of Medicine is currently exploring the possibility of clinical trials for this approach. However, further research is also required to better understand the role of Golgi stress in cancer immunotherapy situations.
