Can lymph nodes increase the success of cancer immunotherapy?

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

The study, published March 16, 2023, in Cellsuggests that leaving the lymph nodes intact until after immunotherapy could increase efficacy against solid tumors, of which only a small fraction currently respond to these newer types of treatments.

Most immunotherapies focus only on reviving T cells in the tumor, where they often become exhausted in their battle against the tumor’s cancer cells. But the new research shows that allowing the treatment to also activate the immune response of the lymph nodes could play an important role in boosting a 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, a researcher 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 usually the first place where metastatic cancer cells appear, and without surgery it can be difficult to tell if the glands contain metastases.

“Immunotherapy is designed to jump-start the immune response, but if we remove nearby lymph nodes before treatment, we essentially remove the key sites where T cells live and can be activated,” Spitzer said, noting that the evidence that supporting the removal of the lymph nodes comes from older studies that predate the use of current immunotherapies.

Target the lymph nodes, not the tumor

Researchers have largely operated under the assumption that cancer immunotherapy works by stimulating the immune cells in the tumor, Spitzer said. But in a 2017 study in mice, Spitzer showed that immunotherapy drugs actually activate the lymph nodes.

“That study changed our understanding of how these therapies might work,” Spitzer said. 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 enter the tumor and kill the cancer cells.

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

The trial included 12 patients whose tumors had not yet spread beyond the lymph nodes. Typically, such patients undergo surgery to remove the tumor, followed by other treatments if recommended.

Instead, patients received a single cycle of an immunotherapy drug called atezolizumab (anti-PD-L1) which is produced by Genentech, a sponsor of the study. A week or two later, Spitzer’s team measured how much the treatment activated the patients’ immune systems.

Treatment also included surgically removing each patient’s tumor and nearby lymph nodes after immunotherapy and analyzing how the immunotherapy affected them.

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

Spitzer attributes part 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 performing detailed analyses.

“It was a really unique opportunity to be able to collect the tissue from surgery shortly after the patients received the drug,” he said. “We could 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 study in patients with late-stage disease, who typically would not benefit from surgery after immunotherapy.

Metastases inhibit the immune response

Another advantage of the study design was that researchers could compare how the treatment affected lymph nodes with and without metastases or a second cancer growth.

“No one had looked at metastatic lymph nodes this way before,” Spitzer said. “We could see that the metastases weakened the immune response compared 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 partly explain the poor performance of some immunotherapy treatments.

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

Another aim of the current study is to determine whether giving immunotherapy before surgery protects against tumor recurrence in the future. Researchers won’t know the answer to that until they’ve had the chance to follow the participants for a number of years.

“My hope is that if we can trigger a proper immune response before the tumor is removed, all those T cells will stay in the body and recognize cancer cells when they come back,” Spitzer said.

Next, the team plans to study better treatments for patients with metastatic lymph nodes, using drugs that are more effective at reactivating their immune responses.

Authors: Additional study authors are: 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, see the article.

financing: 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). See the newspaper for other financiers.

About UCSF: The University of California, San Francisco (UCSF) focuses exclusively on the health sciences and is committed to the global advancement of health through advanced biomedical research, university education in the life sciences and health professions, and excellence in patient care. It includes UCSF Health, which includes three leading hospitals, as well as affiliates throughout the Bay Area. Go to ucsf.edu or view our information sheet.

About Gladstone Institutes: Gladstone Institutes is an independent, non-profit life science research organization that uses visionary science and technology to conquer disease. Founded in 1979, it is located at the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has developed a research model that disrupts the way science is done, funds big ideas and attracts the brightest minds.