Author: Amér Ghali
Editors: Jennifer Baker, Andrés Rivera Ruiz, and Madeline Barron
There is much to appreciate about the way our bodies keep themselves healthy through the array of different immune cell types and their related, yet distinct, methods of protecting us from sickness. From T cells conducting orchestrated attacks on foreign pathogens to B cells producing antibodies which stave off severe illness at the outset of an infection, these cells and their diverse functions resemble a set of chess pieces in the way that they each perform unique tasks in consort with one another to achieve a common objective. However, their goal is not necessarily victory over any one opponent, but rather against all challenges to the immune system, whether external viruses such as COVID-19, or from within, as is the case with cancer.
The field of immunotherapy harnesses the power of the immune system to defeat one of the most common and deadly conditions: cancer. It uses molecules made by the body or in the lab to hone the immune system’s ability to find and destroy cancer cells. Cancer immunotherapy has gained considerable traction in recent years as a potential alternative to chemotherapy and radiation, as the side effects of these classic cancer therapies are often severe and debilitating, while those associated with immunotherapy are relatively mild. Moreover, cancer immunotherapies are versatile and can be adjusted to different patients’ needs based on factors such as their genetic background, other medications they may currently be taking, and how their bodies react to the treatment.
However, while immunotherapy has certainly made notable strides on its path to full adoption, it is not without its own shortcomings and obstacles. Cancer cells are notoriously elusive and complex; they employ a slew of dynamic biochemical techniques to evade being detected and neutralized by the body’s T cells, which bear the brunt of the response against these rogue cells. In a way, T cells function much like a bouncer: they operate by determining if the external molecular signals on a cell’s surface match those of healthy cells by scanning for the signature MHC-I molecule, which indicates that the cell has an “invitation” and is allowed to continue on existing in the body’s “private party”. In contrast, cancer cells do not have this MHC-I “invitation” on their surface and are therefore subject to rejection by the bouncer-like T cell, being targeted for destruction by the T cell’s arsenal of highly potent, toxic chemicals.
To prevent detection by T cells, cancer cells use a variety of methods that prevent the T cell from interacting with their surface and noticing the missing MHC-I “invitation”. For example, a cancer cell may change or hide other external signals that would normally alert T cells to its uninvited existence. Alternatively, a tumor may secrete chemicals that prevent immune cells from leaving the bone marrow, precipitating a veritable “T cell traffic jam” that prevents them from effectively doing their job. However, we are far from fully understanding cancer cells’ cunning, and further investigations are required to understand the mechanisms by which cancer cells impede T cell activity. In doing so, we can identify ways for medical professionals to augment the actions of T cells and other immune-based therapies to overcome cancer’s evasion tactics.
Along with the examples above, cancer cells have distinct biochemical fingerprints that may allow them to circumvent the immune response. For example, cancer cells have higher concentrations of cholesterol molecules embedded in their membrane in comparison to normal cells. Cholesterol influences the overall stability of the cellular membrane, in such a way that more cholesterol results in greater membrane fluidity. Knowing this, it’s natural to wonder: is there a relationship between these distinct characteristics of cancer cells, like cholesterol enrichment, and the efficacy of immunotherapies?
According to a recent study by the Tang Lab at the Swiss Federal Institute of Technology, it’s possible. In this study, the researchers first treated a culture of skin cancer cells with cholesterol supplements. Then, the researchers measured the relative stiffness of the treated cells using a technique known as atomic force microscopy, which uses high-power lasers to scan the physical properties of a surface down to a billionth of a meter. As expected, the researchers found that cancer cells treated with added cholesterol displayed a 40% increase in membrane fluidity compared to those that were not.
Next, the researchers needed to link this finding and its proposed effect on immune cell activity–to do this, researchers cultured skin cancer cells with cytotoxic T cells, which would ordinarily attack the cancer cells and suppress their growth. As expected, when treated with the same cholesterol supplements from the previous experiment, more cancer cells survived their incubation with the T cells.
Having shown the link between higher levels of cholesterol and increased resistance to immune cell activity, the researchers then attempted to address the issue by lowering cholesterol levels in cancer cells, and by extension, the fluidity of their membranes. To do this, they treated cancer cells with an anti-cholesterol drug, MeβCD, before adding in the T cells. They found that the T cells were better able to kill cancer cells following MeβCD treatment, as tumors in mice showed a significant reduction in size following the combination treatment with MeβCD and T cells. Together, these findings suggest that increased levels of cholesterol in the membranes of cancer cells play a role in preventing T cells from launching a more pronounced immunotherapeutic effect.
The explanation for this phenomenon may lie in the mechanism by which T cells conduct their cytotoxic activity. Scientists hypothesize that increased membrane fluidity makes it more difficult for T cells to bind to receptors located on the cancer cell’s membrane, thereby impairing T cells’ ability to scan for the expected MHC-I “invitation” and wage an effective immune response. It is easier for T cells to successfully complete these interactions when cancer cell membranes are less fluid, just as planting a flower in firm soil is easier than doing so in constantly shifting quicksand.
Ultimately, these findings provide valuable insight into the one of the myriad factors that govern cancer progression. Given this newfound understanding of the cholesterol’s role in abetting the resistance of tumor cells to the immune system, investigators and clinicians can pursue these new leads for potential therapeutic approaches. This may take the form of combination therapies, such as the one used in the study, with drugs that lower cholesterol levels in cancer cell membranes followed by T cell-based immunotherapies that are no longer impaired by an inability to firmly bind to the tumor. Additionally, there may also be implications for lifestyle improvements that patients can incorporate in terms of managing cholesterol levels through changes to their diet and levels of exercise. Through these kinds of interventions, we can help our already robust immune system to excel even more when battling challenges like cancer.
Amer Ghali is a local author from Ann Arbor. After graduating from the University of Michigan with a degree in Biomolecular Science in 2020, he has continued working with the Venneti Lab at the Department of Pathology, where he investigates the epigenetic mechanisms of pediatric spinal gliomas. In his spare time he enjoys visiting Barton Dam, hanging out around North Campus, and playing chess online.