Findings from a Mayo Clinic investigation propose that checkpoint immunotherapy could fundamentally alter the immune environment inside lymph nodes once melanoma has infiltrated them. The analysis revealed immunotherapy prompted a reorganization of various immune cell types while modifying the behavior of macrophages—cells capable of either enhancing or inhibiting immune reactions based on their surroundings.
Checkpoint immunotherapy functions by enabling the immune system to identify and combat cancer cells through the inhibition of signals that typically restrict immune activity. Though these therapies have transformed cancer treatment, not every patient experiences benefits, prompting scientists to explore the reasons behind these differing outcomes.
Examining the immune environment
The research, detailed in Communications Biology, may offer insights into why responses to immunotherapy differ. The results imply that how immunotherapy restructures the lymph node environment, rather than its direct impact on individual immune cells, could play a critical role in determining treatment effectiveness. Jessica Lancaster, Ph.D., the study’s lead author and a Mayo Clinic immunologist, noted that cancer treatment extends beyond activating T cells alone; the surrounding environment also plays a key role in their function.
Lymph nodes serve as central hubs where immune cells engage and responses are initiated. They are also common early sites for melanoma metastasis. Using a preclinical melanoma model, Mayo Clinic researchers analyzed lymph nodes draining tumor-affected areas after administering checkpoint immunotherapy. By integrating advanced imaging with cellular and gene-expression techniques, they assessed which cells were present, their locations, and how they evolved with treatment. The findings showed reduced metastatic tumor presence in lymph nodes alongside a reorganization of T cells, B cells, myeloid cells, and structural framework cells.
Macrophage transformations
The study highlighted significant changes in macrophages, immune cells that typically remove damaged or dying cells but can be manipulated by tumors to dampen immune activity. Following immunotherapy, macrophages displayed traits of transitioning toward a more immune-activating state. Additionally, researchers detected increased spatial separation between macrophages and T cells, potentially minimizing inhibitory interactions.
The project expands on Mayo Clinic’s established research into immune checkpoints. Dr. Lancaster’s team worked with Haidong Dong, M.D., Ph.D., a cancer immunology specialist whose prior work advanced understanding of the checkpoint pathway examined here. Dr. Dong emphasized that the study demonstrates myeloid cells can also be reprogrammed to bolster the immune fight against cancer.
However, the researchers stressed that the study used a preclinical model and does not perfectly mirror melanoma progression in humans. Additional studies will be necessary to confirm whether similar immune changes occur in patients and how they correlate with treatment efficacy. The work was funded by the National Institutes of Health and other sources.