Targeting myeloid cells to enhance cancer immunotherapy

Mayo Clinic researchers have identified a specific immune cell that can be targeted to give a boost to standard immunotherapies for cancer. Two research teams, working collaboratively but using distinct approaches, found that "first-responder" immune cells known as myeloid cells can be manipulated to enhance the activity of tumor-killing T cells.

The finding suggests that enhanced myeloid cells may boost certain immune checkpoint therapies, which are the standard of care for some cancers but may not have lasting effects. A clinical trial is now being developed at Mayo Clinic to test the enhanced cells in patients.

In a study in Journal for ImmunoTherapy of Cancer, Mayo Clinic researchers detailed how they found a way to boost cancer-killing T cells. The goal was to improve treatments that interfere with immunosuppressive proteins, PD-1 and PD-L1, which together suppress T cells' ability to fight cancer. Even though PD-L1 immunotherapies aim to block PD-L1, the researchers found that the molecule can persist through a natural recycling process that puts it back in play.

Our study found the importance of the recycling process, and we present a way to address it."

Haidong Dong, M.D., Ph.D., cancer immunology researcher at Mayo Clinic Comprehensive Cancer Center and principal investigator of the study

The research team developed an antibody, H1A, which they found can reduce PD-L1 in human myeloid cells and keep it from recycling. The protein PD-L1 is present in abundance on the surface of myeloid cells. When the protein was prevented from recycling on myeloid cells, the cells then boosted the action of cancer-killing T cells.

"We now have a tool that can completely remove PD-L1 and in doing so we have more myeloid cell activation," says lead author of the study, Michelle Hsu, who conducted the research as her graduate thesis at Mayo Clinic Graduate School of Biomedical Sciences. "Identifying the myeloid cell was an unexpected discovery," she says.

Another Mayo Clinic team took a different approach and arrived at a similar conclusion about the importance of myeloid cells. A research team led by immunology researcher Jessica Lancaster, Ph.D., at Mayo Clinic in Arizona, reported in iScience that macrophages, a type of myeloid cell, play a role in activating the cancer-killing T cells.

Using the complex approach of live-cell microscopy, the team found that in mice, T cells interact closely with the macrophages and create a molecular environment that has greater capacity to kill a tumor.

"This is a paradigm shift for PD-L1 immunotherapy, which has traditionally focused on the interaction of the tumor and the T cells," says Dr. Lancaster. "We found that it's important to co-opt the macrophage, which acts as another immune cell partner." 

Further, says lead author Tina Kwok, who completed the studies during her Ph.D. research at Mayo Clinic, "We can directly reprogram tumor macrophages to be more pro-inflammatory. They can become better T-cell activators and drive better tumor control. Reprogramming of the macrophage may be key to being able to prevent therapy resistance and change outcomes for patients."

Based on the findings from both labs, a phase 1 clinical trial of H1A is being planned. The research could ultimately better address resistance to immunotherapy and expand treatment options for people with cancer.

Review the studies in Journal for ImmunoTherapy of Cancer and iScience for a complete list of authors, disclosures and funding.