PD-1 blockade checkpoint immunotherapy has become the go-to treatment for advanced melanoma. It works for 40% of patients, but the other 60% develop resistance and their tumors grow back. A team of researchers has found a new approach to improve this therapy by focusing on the communication between immune cells in the tumor.Researchers from the University of California, Irvine have discovered a new approach to improve the effectiveness of cancer therapy by addressing the communication between immune cells within the tumor. The study, published in the journal Cancer Cell, found that while PD-1 blockade triggers a powerful anti-tumor response in CD8+ T cells, it also leads to an increase in T regulatory cells, which weakens the immune response against the tumor.
There is a dual challenge in treating cancer, with one aspect targeting the tumor and the other regulating the immune system.
Francesco Marangoni, assistant professor of physiology & biophysics at UC Irvine, explained that their recent study found that CD8+ T cells, activated by PD-1 blockade for melanoma treatment, also interact with T regulatory cells. This interaction leads to a decrease in the immune response against the tumor. Marangoni described the communication between these cells as similar to two telephone landlines connected by a cable. Cutting the cable, or disrupting this communication, could potentially improve cancer treatment.
CD8+ T cells are unable to signal the T regulatory cells to suppress the immune response to cancer. The team’s research focused on the communication process between CD8+ T and T regulatory cells within tumors and discovered the crucial role of a molecule called ICOS, necessary for T cell activation. Their findings showed that by blocking ICOS and PD-1, CD8+ T cells were able to enhance their activity against the tumor, but were no longer able to activate T regulatory cells. First author Shannon Geels from UC I stated, “Our research has uncovered a potential explanation for why some patients develop resistance to checkpoint blockade treatment.”The Department of Physiology & Biophysics’ graduate student researcher in Irvine discovered that cell communication plays a role in immunotherapy failure and that targeting specific messages exchanged by immune cells can improve its effectiveness.”
The next step in the study is to unravel the intricate communication network between different cell types in a tumor.
Marangoni stated, “We don’t believe there is just one ‘phone cable’ to cut. Our results offer a potential avenue for enhancing our comprehension of how all cell types communicate within a tumor. This will help us identify the messages that hinder.the full potential of CD8+ T cells when they are activated by PD-1 blockade, in order to maximize the benefits for patients.”
Other members of the UC Irvine team included faculty and graduate students from various departments such as physiology & biophysics, biological chemistry, dermatology, and developmental & cell biology. Additionally, researchers from the Institute for Immunology, the Center for Complex Biological Systems, and the NSF-Simons Center for Multiscale Cell Fate Research were involved. Faculty from Saint John’s Cancer Institute in Santa Monica, the University of Alabama at Birmingham, and Massachusetts General Hospital and Harvard Medical School also contributed to this project.
This research received support from pilot fundingThe Chao Family Comprehensive Cancer Center, the National Science Foundation, the U.S. Department of Defense, and the National Institutes of Health are among the organizations that provide grants for this research.
