What is it about?
Immune checkpoints are protein molecules found on immune cells, designed to prevent the immune system from attacking the body's own cells. However, as cancer cells are abnormal, the immune system identifies them as foreign and attempts to eliminate them. To evade immune destruction, cancer cells can activate these immune checkpoints, thereby suppressing anti-tumor immune responses. As a result, using specific monoclonal antibodies to block these activated immune checkpoints could enable the immune system to effectively target and destroy cancer cells. Immune checkpoint inhibitors are thus being extensively researched for cancer treatment. These include monoclonal antibodies like Ipilimumab for blocking the CTLA-4 immune checkpoint, Pembrolizumab and Nivolumab for inhibiting PD-1, and Atezolizumab, Avelumab, and Durvalumab for targeting PD-L1. In some cases, combinations of more than one inhibitor are employed. Numerous clinical trials are underway to assess the combination of chemotherapy and radiotherapy with immune checkpoint inhibitors. Surprisingly, despite significant interest in immune checkpoint inhibition, the exact mechanisms by which cancer cells activate immune checkpoints remain unclear.
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Photo by National Cancer Institute on Unsplash
Why is it important?
Prof. Mittra’s group, at Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Mumbai previously reported that cell-free chromatin particles (cfChPs), fragments of chromosomal material released from dying cells, can infiltrate healthy cells and trigger two cancer hallmarks: DNA damage and inflammation. Given that immune escape through immune checkpoint activation is another key cancer hallmark, his team investigated whether cfChPs might also activate immune checkpoints. Remarkably, they found this to be the case. Their recent publication revealed that treating isolated human lymphocytes with cfChPs from the sera of cancer patients significantly activated immune checkpoints like PD-1, CTLA-4, LAG-3, NKG2A, and TIM-3. This finding was further validated in vivo; mice intravenously injected with cfChPs showed upregulation of these checkpoints in their spleen immune cells. Similar upregulation was observed when isolated lymphocytes were exposed to conditioned medium containing cfChPs from hypoxia-induced dying cancer cells. Importantly, they demonstrated that this activation could be inhibited by pre-treating the medium with different cfChPs deactivating agents. Among these, the pro-oxidant combination of Resveratrol and metallic Copper (R-Cu) showed the most promise, deactivating cfChPs via free radicals and suggesting its potential as an immune checkpoint suppressor.
Perspectives
Current immune checkpoint inhibitors are associated with significant toxicity and high costs, limiting their use, particularly in resource-limited settings. We propose that R-Cu might be a viable alternative to monoclonal antibody-based inhibitors. R-Cu offers several advantages: it can simultaneously down-regulate multiple immune checkpoints; it has exhibited low toxicity; it is relatively inexpensive; it can target other cancer hallmarks beyond immune checkpoints; and it has shown efficacy in various human conditions, including advanced oral cancer. We advocate for R-Cu to be compared with traditional immune checkpoint inhibitors in well-designed randomized clinical trials.
Professor Indraneel Mittra
Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer
Read the Original
This page is a summary of: Cell-free chromatin particles released from dying cancer cells activate immune checkpoints in human lymphocytes: implications for cancer therapy, Frontiers in Immunology, January 2024, Frontiers,
DOI: 10.3389/fimmu.2023.1331491.
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