Immunotherapy reshapes immune cell interactions in melanoma-affected lymph nodes

A new study from Mayo Clinic suggests checkpoint immunotherapy may reshape the immune environment within lymph nodes after melanoma has spread to them. Researchers found that treatment reorganized several types of immune cells and changed the behavior of certain cells, called macrophages, that can either support or suppress an immune response depending on their environment.

Checkpoint immunotherapy helps the immune system recognize and attack cancer by blocking signals that can restrain immune cells. While these treatments have transformed cancer care, not all patients benefit, and researchers are working to understand why responses vary.

The study, published in Communications Biology, could help answer that question. The findings suggest that how immunotherapy reshapes the lymph node environment - not just how it affects individual immune cells - may be an important part of the body's response to treatment.

"We're learning that treating cancer isn't only about the T cells themselves. We also have to think about the environment they're working in," says Jessica Lancaster, Ph.D., senior author of the study and a Mayo Clinic immunologist. "Our study suggests that you may need to renovate the entire neighborhood to create an effective antitumor response."

Looking beyond T cells

That neighborhood includes the lymph nodes, which are organized hubs where immune cells interact and immune responses begin. Lymph nodes also can be among the first places melanoma spreads.

Using a preclinical model of melanoma metastasis, Mayo Clinic researchers studied lymph nodes that drain the area around a tumor following checkpoint immunotherapy. They combined advanced imaging with cellular and gene-expression analyses to examine which cells were present, where they were located and how they changed with treatment.

Treatment reduced the amount of metastatic tumor in the lymph nodes and reorganized T cells, B cells, myeloid cells and cells that provide the lymph node's structural framework.

Researchers saw particularly notable changes in macrophages, immune cells that normally help clear damaged and dying cells but can be influenced by tumors to suppress the immune response.

After checkpoint immunotherapy, macrophages showed signs of shifting toward a more immune-stimulating state. Researchers also observed greater physical separation between macrophages and T cells, which may reduce suppressive interactions.

The work builds on Mayo Clinic's long-standing research into immune checkpoints. Dr. Lancaster's team collaborated with Haidong Dong, M.D., Ph.D., a Mayo Clinic cancer immunology researcher whose earlier work contributed to understanding the checkpoint pathway targeted in this study.

For years, much of the focus has been on how these treatments help T cells attack cancer. What's been missing from the big picture is the role of myeloid cells. This study shows that these cells can also be reprogrammed to help stimulate the immune response against cancer."

Dr. Haidong Dong, M.D., Ph.D., a Mayo Clinic cancer immunology researcher

A broader view of immunotherapy

The findings suggest that effective immunotherapy may depend not only on activating T cells but also on creating an environment where different immune cells can work together against cancer.

"The lymph node is the site of immune activation," Dr. Lancaster says. "Understanding what happens there could help us think differently about how to design therapies for different types of cancer."

The researchers caution that the study was conducted in a preclinical model and does not fully replicate how melanoma develops and spreads in people. Future studies will be needed to determine whether the same immune changes occur in patients and how they relate to treatment response.

The research was supported by the National Institutes of Health, the Miltenyi Biotec Spatial Biology Award, David F. and Margaret T. Grohne Cancer Immunology and Immunotherapeutics Research Program within Mayo Clinic Comprehensive Cancer Center, Mayo Clinic Breast Cancer Specialized Program of Research Excellence (SPORE) and Mayo Clinic Hepatobiliary Cancer SPORE.