Researchers have caught tumor-associated immune cells called macrophages in the act of stealing checkpoint inhibitor antibodies away from their intended T cell targets, and blocking this thievery led to improved therapeutic responses in tumor-bearing mice. Immune checkpoint blockade therapies have been shown to be tremendously helpful in treating multiple malignancies including non-small cell lung, bladder, and skin cancers, but not all patients respond to these treatments. Here, Sean Arlauckas and colleagues discovered one potential reason why checkpoint blockade antibodies sometimes fail to prevent T cell exhaustion, and as a result cannot unleash the immune system against cancer.
The researchers used intravital imaging to peer inside tumors in living mice, where they observed macrophages that removed checkpoint blockade antibodies from T cells. Similar antibody-stealing occurred in a culture system composed of human cells together with the currently approved cancer immunotherapy, nivolumab. Interestingly, macrophages typically gobble up invading pathogens and debris, though the researchers determined that the cells were capturing checkpoint blockade antibodies through a separate process involving a surface receptor called FcγR. Blocking FcγR allowed checkpoint inhibitor antibodies to interact with T cells in both rodents and human cells growing in culture. What's more, co-treatment with checkpoint inhibitors and FcγR blocking antibodies led to a 100% response rate in a mouse model of cancer that typically displays substantial animal-to-animal variability in therapeutic outcomes. The authors say therapeutic regimens designed to target tumor macrophages may enhance the activity of immunotherapies, providing additional benefit by increasing immune checkpoint blockade drug delivery.
Article: In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy, Sean P. Arlauckas et al., Science Translational Medicine, doi: 10.1126/scitranslmed.aal3604, published 10 May 2017.