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Can Lymph Nodes Boost the Success of Cancer Immunotherapy?

New data from a clinical trial show therapies may activate lymph nodes to produce tumor-tackling T cells

Cancer treatment routinely involves taking out lymph nodes near the tumor in case they contain metastatic cancer cells. But new data from a clinical trial by researchers at UC San Francisco and Gladstone Institutes shows that immunotherapy can activate tumor-fighting T cells in these nearby lymph nodes.

The study, published in the March 15, 2023, issue of Cell, suggests that leaving lymph nodes intact until after immunotherapy could boost efficacy against solid tumors, only a small fraction of which currently respond to these newer types of treatments.

Most immunotherapies are aimed only at reinvigorating T cells in the tumor, where they often become exhausted battling the tumor’s cancer cells. But the new research shows that allowing the treatment to activate the immune response of the lymph nodes as well can play an important role in driving positive response to immunotherapy.

“This work really changes our thinking about the importance of keeping lymph nodes in the body during treatment,” said Matt Spitzer, PhD, an investigator for the Parker Institute for Cancer Immunotherapy and Gladstone-UCSF Institute of Genomic Immunology and senior author of the study.

Lymph nodes are often removed because they are typically the first place metastatic cancer cells appear, and without surgery, it can be difficult to determine whether the nodes contain metastases.

“Immunotherapy is designed to jump start the immune response, but when we take out nearby lymph nodes before treatment, we’re essentially removing the key locations where T cells live and can be activated,” Spitzer said, noting that the evidence supporting the removal of lymph nodes is from older studies that predate the use of today’s immunotherapies.

Aim for the Lymph Nodes, Not the Tumor

Researchers have assumed that cancer immunotherapy works by stimulating the immune cells within the tumor, Spitzer said. But in a 2017 study in mice, Spitzer showed that immunotherapy drugs are actually activating the lymph nodes. 

“That study changed our understanding of how these therapies might be working,” said Spitzer. Rather than the immunotherapy pumping up the T cells in the tumor, he said T cells in the lymph nodes are likely the source for T cells circulating in the blood. Such circulating cells can then go into the tumor and kill off the cancer cells. 

“If we can activate a good immune response before the tumor is taken out, all those T cells will stay in the body and recognize cancer cells if they come back,” added Spitzer.

Having shown that intact lymph nodes can temper cancer’s hold in mice, Spitzer’s team wanted to know whether the same would prove true in human patients. They chose to design a trial for patients with head and neck cancers because of the high number of lymph nodes in those areas.

The trial enrolled 12 patients whose tumors hadn’t yet metastasized past the lymph nodes. Ordinarily, such patients would typically undergo surgery to remove the tumor, followed by other treatments if recommended. 

Instead, the group at UCSF gave the patients a single cycle of an immunotherapy drug called atezolizumab (anti-PD-L1). The drug is produced by Genentech, who also sponsored the trial. A week or two later, the researchers measured how much the treatment activated the patients’ immune systems.

The treatment also included surgically removing each patient’s tumor and nearby lymph nodes after immunotherapy. The researchers analyzed the tissue to see how the immunotherapy treatment had affected it. 

The team found that, after immunotherapy, the cancer-killing T cells in the lymph nodes began springing into action. They also found higher numbers of related immune cells in the patients’ blood.

Spitzer attributes some of the trial’s success to its design, which allowed the team to get a lot of information from a small number of patients by looking at the tissue before and after surgery and running detailed analyses.

“Being able to collect the tissue from surgery shortly after the patients had been given the drug was a really unique opportunity,” he said. “We were able to see, at the cellular level, what the drug was doing to the immune response.”

That kind of insight would be challenging to get from a more traditional trial in patients with later-stage disease, who would not typically benefit from undergoing surgery after immunotherapy.

Metastases Inhibit Immune Response

Another benefit of the study design was that it allowed researchers to compare how the treatment affected lymph nodes with and without metastases.

“No one had looked at metastatic lymph nodes in this way before,” said Spitzer. “We could see that the metastases impaired the immune response relative to what we saw in the healthy lymph nodes.”

It could be that the T cells in these metastatic nodes were less activated by the therapy, Spitzer said. If so, that could explain, in part, the poor performance of some immunotherapy treatments.

Still, the therapy prompted enough T-cell activity in these lymph nodes to consider leaving them in for a short period of time until treatment ends. “Removing lymph nodes with metastatic cancer cells is probably still important but taking them out before immunotherapy treatment may be throwing the baby out with the bathwater,” said Spitzer.

The team plans to study how that information can guide better treatment for patients with metastatic lymph nodes, using drugs that would be more effective at reactivating their immune responses.

A subsequent goal of the trial is to determine whether giving immunotherapy before surgery protects against the recurrence of tumors in the future. The researchers won’t know the answer to that until they’ve had a chance to monitor the participants for several years.

“My hope is that if we can activate a good immune response before the tumor is taken out, all those T cells will stay in the body and recognize cancer cells if they come back,” he said.

Authors: Additional authors on the study include: Maha K. Rahim, Trine Line H. Okholm, Kyle B. Jones, Elizabeth E. McCarthy, Jacqueline L. Yee, Diana M. Marquez, Iliana Tenvooren, Patrick Ha, and Katherine Wai of the Departments of Otolaryngology-Head and Neck Surgery and Microbiology and Immunology and the Helen Diller Family Comprehensive Cancer Center (HDFCCC), Matthew F. Krummel of HDFCCC, the Department of Pathology and the Parker Institute for Cancer Immunotherapy, Lawrence Fong of HDFCCC, the Department of Medicine, and the Parker Institute for Cancer Immunotherapy, Alain P. Algazi of HDFCCC and the Department of Medicine, Alexander Cheung of the Department of Medicine, Alexis J. Combes of UCSF CoLabs, the Department of Medicine, and the Department of Pathology, and Stanley J. Tamaki, Brittany R. Davidson, Vrinda Johri, and Bushra Samad of UCSF CoLabs. For other authors, please see the paper.

Funding: National Institutes of Health grants (DP5 OD023056, R01 DE032033,S10 OD025187, S10 OD018040, and K23DE029239), along with and funding from Roche/Genentech through the immunotherapy Centers of Research Excellence (imCORE). For other funders, please see the paper.

About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF’s primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. UCSF School of Medicine also has a regional campus in Fresno. Learn more at or see our Fact Sheet.

About Gladstone Institutes: Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds.


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