Researchers at Winship Cancer Institute of Emory University have identified a novel type of immune cell, called the stem-like CD4 T cell, that plays a pivotal role in anti-tumor immunity. The pre-clinical findings, published in Nature, highlight the potential to activate these cells to fight tumors more effectively, offering new hope for broader treatment success, particularly in patients with cancer that is unresponsive to current immunotherapies.

Led by Haydn T. Kissick, PhD, researcher in the Cancer Immunology Research Program at Winship Cancer Institute and assistant professor in the Department of Urology at Emory University School of Medicine, the study reveals that these stem-like CD4 T cells reside in the lymph nodes near tumors. While capable of driving a powerful anti-tumor response, these cells often remain inactive, limiting the immune system's response to the tumor.

The stem-like CD4 T cells have the ability to renew themselves and transform into different immune cell types. These cells 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 a common immunotherapy treatment called 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."

The 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 explains.

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.

"We still have many questions to answer and challenges to overcome," says Kissick. "I feel confident that Winship of Emory is the place for these discoveries and advancements to be made and to determine how to leverage these mechanisms to target the cells and direct them to do what we need them to do to turn on the immune response. 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."

Cardenas MA, Prokhnevska N, Sobierajska E, Gregorova P, Medina CB, Valanparambil RM, Greenwald R, DelBalzo L, Bilen MA, Joshi S, Naryan V, Master VA, Sanda MG, Kissick HT.
Differentiation fate of a stem-like CD4 T cell controls immunity to cancer.
Nature. 2024 Oct 23. doi: 10.1038/s41586-024-08076-7