T cells fighting cancer cells. (stock image)
Chrystal M. Paulos, PhD
Researchers at Winship Cancer Institute of Emory University have discovered that B cells — immune cells best known for producing antibodies — can help train cancer-fighting T cells while those cells are being prepared for treatment.
The finding could lead to a practical new way to produce stronger T cell therapies, particularly for solid tumors, which have been more difficult to treat with these cellular therapy approaches than many blood cancers.
The study, “TLR9 Agonists Potentiate Adoptive T Cell Therapy in Cancer through a B Cell–CD2 Costimulatory Axis,” was published in Cancer Research, a journal of the American Association for Cancer Research.
Ayana T. Ruffin, PhD
Ayana T. Ruffin, PhD, a postdoctoral fellow in the Paulos Lab at Winship, is the study’s first author. The senior and corresponding author is Chrystal M. Paulos, PhD, co-leader of Winship’s Cancer Immunology Research Program, director of translational research for cutaneous malignancies and the David H. Lawson Professor in Cancer Research.
“We have spent two decades engineering T cells to be better cancer killers,” Paulos says. “It turns out the T cell was never working alone. The B cell sitting next to it in the flask was coaching it, and we had been ignoring that conversation entirely. Once we knew to listen, we found the exact molecule they were speaking through.”
Helping T cells stay strong
Some cell therapies work by collecting a patient’s own T cells, growing or modifying them in a laboratory and returning them to the patient to recognize and attack cancer. Because the cells serve as a living treatment, their condition when they leave the laboratory can help determine how well they work.
This has been a significant challenge in treating solid tumors. T cells can become worn out and lose their ability to continue fighting cancer.
The Winship-led team found that activating B cells gave the antitumor T cells an important boost, while they were growing. The B cells communicated with the T cells through a molecule called CD2 that is visible on their surface. That interaction helped the T cells remain healthier, resist becoming worn out and kill cancer cells more effectively.
In mouse models, the strengthened T cells cleared established solid tumors.
The researchers initially expected the effect to involve one of the signals already commonly used to strengthen T cells, such as CD28 or ICOS. Instead, they found that the benefit depended on a different signal that had largely been overlooked in the development of cell therapies. When researchers blocked that CD2 signal, the benefit disappeared.
The team also observed the interaction in human T and B cells. In addition, higher levels of CD2 in human tumors were associated with better survival among groups of patients with melanoma, breast cancer and lung cancer. Researchers will continue studying whether it could eventually help identify patients who are more likely to benefit from immunotherapy.
A practical approach
The discovery is especially promising because the B cells could be activated while the T cells are being prepared in the laboratory. The approach would not require giving the immune-stimulating compound directly to the patient.
Compounds called ‘Bites’ that unite T and B cells have previously been tested in patients with limited success and some side effects. Using the compound only during the manufacturing process could potentially strengthen the T cells without exposing the patient directly to it.
Gregory B. Lesinski, PhD, MPH
“What makes this finding actionable is that every piece of it already exists,” says Gregory B. Lesinski, PhD, MPH, Winship’s associate director for basic research and shared resources and professor and vice chair for basic research in the Department of Hematology and Medical Oncology at Emory University School of Medicine. “The drug has been in patients. The manufacturing capability is here at Winship. We are not waiting on a decade of development to test whether this makes cell therapy work better for people with solid tumors.” Dr. Lesinski is a corresponding author of this study as well.
The findings are preclinical and do not change treatment for patients today. Additional research is needed to determine whether the approach can be used safely and effectively in therapies manufactured for clinical trials.
The researchers’ next steps include testing the approach on the larger scale needed to produce treatments for patients. They will also explore whether B cell coaching can strengthen different forms of cell therapy and whether it works against cancers beyond melanoma.
In collaboration with co-senior and corresponding author Avery D. Posey Jr., PhD, of the University of Pennsylvania Perelman School of Medicine, the researchers also built the newly identified signal directly into engineered T cells. In preclinical experiments, those cells killed pancreatic cancer cells more effectively than cells made using a more common design.
The team will also study whether B cells already present inside tumors could be activated to support cancer-fighting T cells after they enter the body.
Building on earlier Winship discoveries
The research builds on a 2022 study led by Aubrey S. Smith, PhD, then a graduate student in the Paulos lab and a co-author of this new paper. That study found that B cells could strengthen cancer-fighting T cells but did not determine how they did it. The new research identifies the signal responsible and shows how it might be used to improve future therapies.
The findings also align with research published in Cancer Cell in 2025 by the Paulos and Lesinski laboratories. That study found another way that T cells and B cells can work together to produce lasting immune responses against melanoma.
Together, the studies suggest that B cells are not simply bystanders in T cell therapy. They may play an important and previously underrecognized role in helping cancer-fighting T cells work effectively.
Winship led the new study’s concept, experiments, investigation of the underlying mechanism and manuscript development. The research used the Emory Integrated Genomics Core and the Pediatrics/Winship Flow Cytometry Core. Patient tumor tissue used in the study was collected through a Winship Institutional Review Board-approved protocol.
Other Emory and Winship contributors include Vasili Toliopoulos, Aubrey S. Smith, PhD, Soundharya Kumaresan, Megan M. Wyatt, PhD, Meredith Salzinger, Anna C. Cole, PhD, Megen C. Wittling, Rachel L. Mason, James H. Carmouche III, Mahmoud A. Adelbary and Yuan Liu, PhD, of the Winship Biostatistics Shared Resource.
The research was supported by National Cancer Institute grants R01 CA300792, R01 CA287866, R01 CA275199 and P30 CA138292, the Winship Postdoctoral Scholar Award, a Cancer Research Institute Fellowship and a Burroughs Wellcome Fund Postdoctoral Enrichment Program award.