Newly discovered “stem-like CD4 T cells” play a pivotal role in anti-tumor immunity, according to preclinical work by researchers at the Winship Cancer Institute of Emory University. The researchers say that activating these cells to fight tumors more effectively could improve immunotherapy.
Their findings are published in Nature and was led by Haydn T. Kissick, PhD, a researcher in the Cancer Immunology Research Program at Winship.
Immunotherapies are a huge success, and they have increasingly been considered as first-line treatments for most cancers. But they only work in a subset of patients. Finding out who they work on and how to make them more effective is therefore a major area of research and drug development.
The world market for immunotherapies is estimated to be worth $285 billion now, and expected to double by 2030. This field includes some of the world’s top selling drugs, including Merck’s Keytruda (pembrolizumab).
The Winship study reveals that these stem-like CD4 T cells reside in the lymph nodes near tumors and are capable of driving a powerful anti-tumor response. However, these cells often remain inactive, limiting the immune system’s response to the tumor.
The team’s findings suggest that almost all patients have this stem-like CD4 T cell in the lymph nodes surrounding their tumors. “Understanding how to teach these cells to switch between the active and idle states could identify new ways to treat many more patients with immunotherapy,” Kissick said.
Stem-like CD4 T cells can renew themselves and transform into different immune cell types. They are marked by two specific proteins, PD1 and TCF1, which help determine their behavior, including self-renewal and regulation. In lab models, activating these cells made PD1 blockade more effective against cancer.
“In around 10% of patients where the stem-like CD4 cell is active, there is a far more vigorous immune response to the cancer,” says Kissick. “These patients survive longer after surgery and are much more likely to respond to checkpoint immunotherapy. However, the challenge we identified is that in most patients, this cell remains in a suppressive state, which essentially tells the immune system to remain idle and ignore the tumor.”
First author Maria Cardenas emphasizes the significance of overcoming this suppression: “Most importantly, while finding the immune system of patients with cancer in this idle state is common, we discovered that the stem-like CD4 T cell is capable of switching to an active state. It can restart a powerful anti-tumor immune response and enhance responsiveness to PD1 blockade in animal models.”
Future exploration of this discovery is needed to determine how to turn the cells’ immune response on and keep it on. Researchers aim to use mRNA and lipid nanoparticle (LNP) technology to re-program these stem-like CD4 T cells, effectively removing the brakes on the immune response to cancer.
Said Kissick, “We have all the pieces of the puzzle here, it’s just a matter of putting them together. Our Phase I Clinical Trials Unit is robust, and we have the contributions of physicians and patients here too.”
