Cancer biologists bring in the B-cell reinforcements for immunotherapy

by Isabella Davis, Salk Institute

edited by Sadie Harley, reviewed by Robert Egan

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Cancer is the second-leading cause of death in the United States, according to a 2026 Cancer Research Institute report. Cancer biologists are keenly aware of this statistic, as it drives innovations that revolutionize cancer care—innovations like immunotherapy. Immunotherapy fights cancer using the body's own immune system, often by boosting the performance of specialized adaptive immune cells called T cells.

Yet not all patients benefit from standard-of-care T cell immunotherapies. Salk Institute scientist Daniel Hollern wants to change that—and he thinks B cells offer new pathways to enhance the immune system's attack on cancer cells. Hollern's lab is working to close the research gap that has shrouded B cells in mystery and prevented them from reaching their full clinical potential.

His latest study, published in Cell Reports, reveals that B cells play a multifaceted role in promoting T cell antitumor activity.

The study is the first to show that B cells can regulate killer T cell function, prompting a slew of new questions about how these interactions work. The insights lay the foundation for harnessing B cells in immunotherapy, which has the potential to radically change the future of cancer care.

"B cell responses have repeatedly been associated with better outcomes in people with cancer, but association alone cannot tell us what those cells are doing," says Hollern, senior author of the study and assistant professor and Frederick B. Rentschler Developmental Chair at Salk.

"Our study begins to provide a mechanistic explanation: B cells can help bring cancer-killing T cells into tumors, organize them, and enhance their cytotoxic function."

What are T cells and B cells?

The immune system has many cells, commonly divided into innate and adaptive categories. Innate immune cells are typically the first line of defense, responding quickly and broadly to any invader. Adaptive immune cells, like T and B cells, are more specialized—they react more slowly, more specifically and for longer periods.

T cells have different jobs—some coordinate the immune system's response to intruders, and some eliminate infected and cancerous cells. CD4⁺ T cells coordinate or help, while CD8⁺ T cells kill. Historically, CD8⁺ T cells were thought to be activated through support from CD4⁺ T cells and innate immune cells called dendritic cells.

But growing evidence from Hollern's lab shows that B cells may play a part in CD8⁺ T cell activation. Because B cells are best known for producing antibodies rather than directly killing tumor cells, their ability to organize and activate cytotoxic T cell responses has received far less attention.

Regardless, B cells play an essential role in the immune response—chiefly by making proteins called antibodies, which are used to identify, target and destroy pathogens and cancer cells. Emerging research also suggests that B cells can help predict patient outcomes and treatment response.

Yet the mechanistic details of how B cells respond to cancer have remained a mystery.

"The field of cancer biology has been missing an opportunity to harness a major regulator of immunity—B cells," says Hollern. "We only really started appreciating antitumor B cell function in the last several years. It's time to start closing the gap."

How are B cells functioning in the cancer response?

The study starts with CD40, a protein that lives on the surface of immune cells like B cells, macrophages and dendritic cells. CD40 interacts with CD40 ligand, a protein counterpart that lives primarily on T cell surfaces. This signaling pathway is thought to have a major impact on the occurrence of an immune response, including against cancer.

In fact, there are active CD40-based drug trials for triple-negative breast cancer—a hard-to-treat breast cancer that lacks the three genetic markers most breast cancer drugs target.

"CD40 is becoming an important clinical target, so we wanted to understand what CD40 activation actually does to B cells in the context of cancer," says co-first author Monika Quackenbush, a graduate student researcher in Hollern's lab.

The researchers used a mouse model of triple-negative breast cancer to investigate the interactions between CD40 and B cells. As they investigated, three discoveries emerged.

First, they found that CD40 agonist treatment produced a B cell-dependent antitumor response in high-mutation-burden breast cancer models. This antitumor response suggests the presence of many potential mutation-derived neoantigens—abnormal proteins on cancer cell surfaces.

Second, they found that B cells could help recruit CD8⁺ T cells to tumors and direct how they organize themselves once inside. Finally, they found that B cells could directly signal to CD8⁺ T cells to turn on their killer functions.

"Altogether, our results show that B cell responses to neoantigens and CD40 stimulation can facilitate CD8⁺ T cell tumoral responses, highlighting the influence B cells can have on CD8⁺ T cells," says co-first author Kendrick Nguyen, a graduate student researcher in Hollern's lab.

Where do future cancer research and care go now?

The evidence keeps pointing to B cells. B cells have been shown to correlate with patient survival and response to therapy, but the Salk study shows that it is not pure correlation—B cells mechanistically and functionally orchestrate antitumor immunity. With these new findings, there is more evidence than ever that B cells may be a potent clinical target for cancer therapeutics.

"We've exposed that B cells can regulate CD8⁺ T cells to drive tumor cell killing," says Hollern, "but we need to figure out how to optimize B cell function to unleash their full capacity to eliminate cancer."

Hollern is a B cell champion, and he sees their potential clearly. His lab will continue to remove the mystery around how B cells are regulated and function in cancer. By closing the gap in the critical mechanisms that determine B cell function, the Hollern lab will develop key therapeutic insights into how to fully exploit B cells to dramatically improve cancer treatment.

"Our work really unearths new questions," says Hollern. "We have made a lot of progress here, but ultimately there's a lot more to explore—then we'll have to connect the dots to harness these foundational biological insights in a therapeutic setting."

Publication details

Kendrick Nguyen et al, B cell responses to CD40 stimulation ignite anti-tumor immunity by activating CD8⁺ T cell cytotoxicity, Cell Reports (2026). DOI: 10.1016/j.celrep.2026.117957

Journal information: Cell Reports

Key medical concepts

B-LymphocytesCD40 AntigensTriple Negative Breast Neoplasms

Clinical categories

OncologyAllergy and immunology Provided by Salk Institute Who's behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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