Researchers have discovered a new type of immune cell known as the stem-like CD4 T cell, which is critical for enhancing anti-tumor immunity. The initial findings from their research suggest that these cells could be activated to combat tumors more efficiently, providing promising possibilities for improved treatment outcomes, especially for patients whose cancers do not respond to existing immunotherapies.
Researchers at the Winship Cancer Institute of Emory University have discovered a new type of immune cell, referred to as the stem-like CD4 T cell, that plays a crucial role in fighting tumors. Their pre-clinical findings, which were published in Nature, underscore the potential to activate these cells for more effective tumor suppression, thereby offering renewed hope for better treatment outcomes, especially for patients with cancers that do not respond to current immunotherapy options.
Led by Haydn T. Kissick, PhD, a researcher affiliated with the Cancer Immunology Research Program at Winship Cancer Institute and an assistant professor at the Department of Urology at Emory University School of Medicine, the study shows that these stem-like CD4 T cells are located in the lymph nodes close to tumors. Although they have the capacity to trigger a strong anti-tumor response, many of these cells stay inactive, which restricts the immune system’s ability to combat the tumor.
The stem-like CD4 T cells are unique in their ability to self-renew and differentiate into various types of immune cells. These cells express two key proteins, PD1 and TCF1, that influence their function, including their ability to renew themselves and modulate their activity. In laboratory models, stimulating these cells was found to enhance the effectiveness of a common immunotherapy treatment known as PD1 blockade against cancer.
“In around 10% of patients where the stem-like CD4 cells are active, there is a significantly stronger immune response to the cancer,” states Kissick. “These individuals tend to have longer survival rates post-surgery and are far more likely to respond positively to checkpoint immunotherapy. The challenge we uncovered is that, in most patients, these cells remain in a suppressive state, effectively instructing the immune system to stay dormant and disregard the tumor.”
Maria Cardenas, the study’s first author, highlights the importance of overcoming this suppression: “While it’s common to find the immune systems of cancer patients in this dormant state, we found that the stem-like CD4 T cell can actually transition to an active state. This switch can reinitiate a strong anti-tumor immune response and boost sensitivity to PD1 blockade in animal studies.”
The research suggests that nearly all patients possess these stem-like CD4 T cells in the lymph nodes surrounding their tumors. “If we can learn how to guide these cells to alternate between active and dormant states, we may find new strategies to treat many more patients using immunotherapy,” Kissick explains.
Further research is necessary to determine how to activate and sustain the immune response of these cells. The team plans to utilize mRNA and lipid nanoparticle (LNP) technology to reprogram the stem-like CD4 T cells, effectively removing the inhibitors on the immune response against cancer.
“There are still numerous questions to address and hurdles to overcome,” says Kissick. “However, I believe that Winship at Emory is well-positioned to uncover these advancements and figure out how to utilize these mechanisms to engage and direct the cells to initiate the immune response we need. We have all the essential components here; now it’s about fitting the pieces together. Our Phase I Clinical Trials Unit is strong, and we have support from physicians and patients alike.”
A collaborative team at Winship Cancer Institute contributed to this study, including Martin Sanda, MD, a researcher in the Cancer Prevention and Control Research Program and chair of the Department of Urology at Emory University School of Medicine; Mehmet Bilen, MD, and Vikram Narayan, MD, from the Discovery and Developmental Therapeutics Research Program; as well as Shreyas Joshi, MD, MPH, and Viraj Master, MD, PhD, from the Cancer Prevention and Control Research Program.
This research was funded by grants from the National Institutes of Health, The Prostate Cancer Foundation, the Cancer Research Institute, and the James M. Cox Foundation.
