A recent study published in Nature Medicine elucidates the reason and suggests a possible solution: tumors in the liver syphon off critical immune cells, rendering immunotherapy ineffective. However, combining immunotherapy with radiotherapy to the liver restored immune cell function and resulted in improved outcomes in mice.
Michael Green, M.D., Ph.D., noticed that his patients fared poorly when their cancer spread to the liver – even more so than when it spread to other parts of the body. Not only that, but these patients received little benefit from transformative immunotherapy treatments.
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“Patients with liver metastases receive little benefit from immunotherapy, a treatment that has been a game-changer for many cancers. Our research suggests that we can reverse this resistance using radiation therapy. This has potential to make a real difference in outcomes for these patients,” says Dr Green, assistant professor of radiation oncology at Michigan Medicine and corresponding author of the research paper.
A multidisciplinary team at the University of Michigan’s Rogel Cancer Center analysed data from 718 patients treated at the center with immunotherapy. Patients had been diagnosed with a variety of cancers, including non-small cell lung cancer, melanoma, urothelial cancer, and renal cell cancer, which had spread to various organs, including the liver and lungs.
Those with liver metastases consistently had poorer immunotherapy responses. The problem was not limited to the liver: these patients had more cancer throughout their bodies than similar patients whose cancer had spread but had not reached the liver.
“The liver is initiating a systemic immunosuppressive mechanism. The mechanism happens in the liver, but we see the systemic impact throughout the body,” says another study author Weiping Zou.
The liver is a frequent site of cancer metastasis. By suppressing certain critical immune cells, it has been shown to impair immune response in autoimmune diseases, viral infections, and organ transplantation.
This was observed in metastatic cancer, where oncologists noted a deficiency of immune response. Green notes that patients with liver metastases treated with chemotherapy or targeted therapies had comparable outcomes to those with other types of metastases.
“It’s unique to immunotherapy,” he says.
When researchers examined the microenvironment of liver metastases, they discovered that the tumors were syphoning off T cells – immune cells that should have been attacking cancer. T cells were being eliminated not only in the liver but also throughout the body, resulting in an immune desert. As a result, the immune system was unable to fight tumors at any location.
The researchers used mice with liver metastases to deliver radiation therapy directly to the liver tumors. This halted the death of T cells. After regenerating T cells, an immune checkpoint inhibitor was able to activate the immune system and eradicate cancer throughout the body, similar to the results observed in non-liver metastases.
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“It’s always a challenge to identify a novel mechanism of immune suppression and find a way to address it. With these promising results, we are now looking to open clinical trials in this space to better understand the mechanisms at play in human tumors,” says Green.
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