Mayo Clinic Develops Novel Approach to Enhance Cancer Immunotherapy by Targeting Myeloid Cells
核心洞察
Mayo Clinic researchers have identified myeloid cells as key targets to enhance cancer immunotherapy, with two collaborative teams demonstrating that manipulating these "first-responder" immune cells can boost tumor-killing T cell activity.
The research teams developed an antibody called H1A (搜索) that prevents PD-L1 (搜索) protein recycling in myeloid cells, leading to enhanced T cell activation and improved cancer-fighting capacity.
A paradigm shift in PD-L1 (搜索) immunotherapy has emerged, showing that macrophages can be directly reprogrammed to become more pro-inflammatory and better T cell activators.
Mayo Clinic researchers have made a significant breakthrough in cancer immunotherapy by identifying myeloid cells as crucial targets for enhancing the effectiveness of standard immune checkpoint therapies. Two collaborative research teams using distinct approaches have demonstrated that manipulating these "first-responder" immune cells can significantly boost the activity of tumor-killing T cells, potentially addressing one of the major challenges in current cancer treatment.
Targeting PD-L1 Recycling in Myeloid Cells
The first research team, led by Dr. Haidong Dong at Mayo Clinic Comprehensive Cancer Center, focused on improving treatments that target immunosuppressive proteins PD-1 (搜索) and PD-L1 (搜索). Published in the Journal for ImmunoTherapy of Cancer, their study revealed a critical limitation in current PD-L1 immunotherapies: the molecule can persist through a natural recycling process that allows it to continue suppressing T cells' cancer-fighting ability.
"Our study found the importance of the recycling process, and we present a way to address it," explains Dr. Dong, the principal investigator of the study.
The research team developed a novel antibody called H1A (搜索), which can reduce PD-L1 (搜索) levels in human myeloid cells and prevent its recycling. Since PD-L1 is present in abundance on myeloid cell surfaces, preventing its recycling led to enhanced activation of these cells, which in turn boosted cancer-killing T cell activity.
"We now have a tool that can completely remove PD-L1 (搜索) and in doing so we have more myeloid cell activation," says Michelle Hsu, the study's lead author who conducted this research as her graduate thesis at Mayo Clinic Graduate School of Biomedical Sciences. "Identifying the myeloid cell was an unexpected discovery."
Macrophage Reprogramming Approach
The second Mayo Clinic team, led by immunology researcher Dr. Jessica Lancaster at Mayo Clinic in Arizona, took a different approach and arrived at similar conclusions about myeloid cell importance. Their research, published in iScience, specifically examined macrophages, a type of myeloid cell, and their role in activating cancer-killing T cells.
Using live-cell microscopy, the team observed that in mice, T cells interact closely with macrophages to create a molecular environment with enhanced tumor-killing capacity. This finding represents a significant shift in understanding how PD-L1 (搜索) immunotherapy works.
"This is a paradigm shift for PD-L1 (搜索) immunotherapy, which has traditionally focused on the interaction of the tumor and the T cells," notes Dr. Lancaster. "We found that it's important to co-opt the macrophage, which acts as another immune cell partner."
Direct Reprogramming of Tumor Macrophages
The research demonstrated that tumor macrophages can be directly reprogrammed to become more pro-inflammatory, making them better T cell activators and improving tumor control. Lead author Tina Kwok, who completed the studies during her Ph.D. research at Mayo Clinic, emphasized the therapeutic potential of this approach.
"We can directly reprogram tumor macrophages to be more pro-inflammatory. They can become better T-cell activators and drive better tumor control," Kwok explains. "Reprogramming of the macrophage may be key to being able to prevent therapy resistance and change outcomes for patients."
Clinical Translation and Future Implications
Based on the findings from both research teams, Mayo Clinic is developing a phase 1 clinical trial to test the H1A (搜索) antibody in patients. This clinical translation represents a significant step toward addressing immunotherapy resistance, a major challenge in current cancer treatment where checkpoint therapies may not have lasting effects despite being the standard of care for some cancers.
The research suggests that enhanced myeloid cells may boost certain immune checkpoint therapies, potentially expanding treatment options for cancer patients. The collaborative approach taken by both teams demonstrates the importance of targeting multiple aspects of the immune system to achieve better therapeutic outcomes.
This breakthrough could ultimately lead to more effective cancer immunotherapies by addressing the fundamental issue of therapy resistance and providing new avenues for treatment in patients who do not respond adequately to current checkpoint inhibitors.