I recommend reading this article from ScienceDaily.
Scientists Crack the Code on Why Some Cancers Resist Immunotherapy
Ann Arbor, MI – A groundbreaking study from the University of Michigan Rogel Cancer Center has shed light on why some cancers are resistant to immunotherapy, a promising treatment that harnesses the body’s own immune system to fight tumors.
The research, led by Dr. Arul M. Chinnaiyan, unearthed the role of the UBA1 enzyme, a known driver of tumor growth, in suppressing the immune response against cancer.
"We’ve seen remarkable clinical successes with immunotherapies, especially with this checkpoint therapy," Dr. Chinnaiyan, director of the Michigan Center for Translational Pathology, explains. "Kidney cancers, some melanomas, and non-small cell lung cancers respond well to immune checkpoint blockade."
This groundbreaking therapy uses drugs to take the brakes off the immune system, allowing it to effectively target and destroy cancer cells.
But the success of immunotherapy isn’t universal. Some cancers, known as "cold" tumors, are notoriously resistant, making treatment a daunting challenge.
"Certain cancers considered ‘cold’ tumors, such as prostate cancer, have fewer intratumoral T cells," Dr. Chinnaiyan clarifies, "so the immune response is weaker than for ‘hot’ tumors with many such cells. While ‘hot’ tumors typically respond well to immunotherapies, ‘cold’ tumors do not."
The ensuing search for solutions led Dr. Chinnaiyan and his team to scrutinize UBA1. Previously recognized for its role in bolstering tumor growth, UBA1 had yet to be explored in the realm of the tumor microenvironment or its impact on the immune response.
Their focus on prostate cancer, a notoriously "cold" tumor with limited responsiveness to immunotherapy, led to a pivotal discovery:
UBA1 emerged as a major roadblock to the immune system’s fight against cancer.
Through a meticulous analysis of tens of thousands of gene data points from prostate tumor samples, the team uncovered a strong negative correlation between UBA1 levels and the expression of interferon-gamma (IFNG), a crucial anti-tumor protein generated by immune cells.
Patients whose tumors exhibited high levels of UBA1 tended to be less responsive to immune checkpoint blockade therapy, resulting in poorer outcomes.
To confirm their findings, the researchers conducted preclinical studies on mice, manipulating UBA1 levels in tumors. The results were striking: higher UBA1 levels fueled tumor growth, while lower levels led to slower tumor progression.
The culprit? UBA1 was effectively blocking the recruitment of CD8+ T-cells, key immune "soldiers" trained to eliminate cancer cells, thereby allowing tumors to evade immune surveillance.
"It’s exciting to have established this link between UBA1 and T-cell recruitment," Dr. Chinnaiyan said.
With a deeper understanding of the mechanisms at play, the team put their discovery to the test.
They combined an existing UBA1 inhibitor, TAK-243, with immune checkpoint blockade therapy in mice.
The results were remarkable: half of the mice treated with this combination saw their tumors completely disappear.
These findings could hold the key to unlocking the potential of immunotherapy for a wider range of cancers and patients.
"We’ve laid the groundwork that this combination of UBA1 inhibitors and ICB could work well in certain cancer types," Dr. Chinnaiyan stated.
The development of more potent UBA1 inhibitors is already underway, and with TAK-243 ready for clinical use, this promising combination therapy might be within reach sooner than anticipated.
