Immunotherapy, one of the latest and most powerful weapons against cancer, holds the ability to stimulate the immune system to identify tumors as intruders within the body and initiate an attack. However, not all patients respond favorably to immunotherapy, and the precise reasons behind this variation often baffle scientists.
On occasion, individuals undergoing immunotherapy encounter side effects that can be managed with the aid of glucocorticoids (GCs), a type of steroid. GCs are commonly employed to regulate immune responses in conditions like asthma, Crohn’s disease, and even COVID-19. Nevertheless, the precise mechanisms by which GCs function remain shrouded in mystery.
Excitingly, researchers from Cold Spring Harbor Laboratory (CSHL) have made significant strides toward unraveling both of these enigmas.
Immunotherapy GCs and Treatment Failures
Their latest research suggests that GCs may indirectly contribute to certain failures in immunotherapy by triggering the production of a protein known as Cystatin C (CyC). Higher levels of CyC have been associated with poorer outcomes in this particular form of therapy.
According to CSHL Assistant Professor Tobias Janowitz, glucocorticoids (GCs) possess remarkable immune-suppressing capabilities, making them a valuable treatment option for autoimmunity, where the immune system mistakenly attacks healthy cells.
“We’ve previously shown that GCs can also break cancer immunotherapy. Now, here’s perhaps a clue into how they’re doing it.”
Janowitz’s laboratory focuses on investigating the comprehensive response of the entire body to cancer. For this particular study, Janowitz collaborated with Sam Kleeman, a Ph.D. student in his lab who transitioned from a physician to a researcher, as well as Hannah Meyer, an Assistant Professor at CSHL specializing in quantitative biology. Together, they embarked on analyzing an extensive genetic dataset obtained from the UK Biobank, consisting of nearly 500,000 volunteers, including cancer patients. Kleeman also reached out to researchers abroad to gather additional patient data, further enriching their investigation.
The researchers made a significant discovery: patients who exhibited a higher propensity to produce Cystatin C (CyC) in response to glucocorticoids (GCs) had a lower overall survival rate and were less likely to benefit from treatment. This finding strongly suggests that the production of CyC within a tumor may contribute to the failure of cancer immunotherapy.
To establish the connection between CyC and cancer, they conducted traditional laboratory experiments. They utilized mice and selectively deleted a gene responsible for CyC production, effectively eliminating its presence in cancer cells. Remarkably, they observed that tumors lacking CyC exhibited slower growth.
“It’s really powerful to come at this from multiple angles and support the findings through many approaches,” Meyer emphasizes. “Clever genetic models gave us some indication of which experiments to design to help us answer the question of what this molecule does.”
Janowitz expresses his intent to continue studying CyC, hopeful that this research will greatly benefit future patients. He adds, “The research has given me an impetus to find out more about the function of this molecule, specifically in the context of cancer immunotherapy. Perhaps its function can be targeted to enhance the success of cancer immunotherapy.”
Source: 10.1016/j.xgen.2023.100347
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