A new study indicates that liver metastases reduce the effectiveness of immunotherapy by triggering apoptosis of tumor-specific T cells. In mice, radiation reversed the loss of T cells and restored the benefits of immunotherapy, providing a potential means of increasing the effectiveness of immunotherapy in patients.

Liver metastases stymie immune checkpoint inhibitors by stimulating tumor-specific CD8+ T cells to undergo apoptosis, a recent study reveals. The research suggests that radiation curbs this effect, offering a possible approach for boosting the effectiveness of immunotherapy.

Clinicians have noted that immune checkpoint inhibitors are less effective in patients with liver metastases than in patients without them, but the mechanism remains unclear. A 2020 study implicated regulatory T cells, which indirectly inhibited antitumor responses in mice with liver metastases. However, researchers suspect that other mechanisms also thwart immunotherapy.

In the new work, researchers analyzed data from more than 1,000 patients with cancer who had been treated with immunotherapy. They found that liver metastases decreased the effect of immune checkpoint inhibitors. For instance, only about 20% of patients with melanoma who had liver metastases lived for 40 months, compared with about 60% of patients with metastases in the brain or other sites.

The researchers then explored the effects of liver metastases on the potency of checkpoint inhibitors in mice. They injected colon tumor cells into the animals and treated them with a PD-L1–blocking compound. The resulting tumors were more than twice as large in mice that had liver metastases than in those with other types of metastases.

To discover why liver metastases reduced the potency of checkpoint inhibitors, the researchers censused tumor-specific CD8+ T cells in mice. They found that animals with liver metastases harbored fewer of these cells in their tumors, blood, and lymph nodes tan mice with other types of metastases. Moreover, large numbers of CD8+; T cells were undergoing apoptosis in the liver.

Metastases also triggered a surge in myeloid cells in the liver, many of which were macrophages. To uncover the roles of these cells, the team gave the mice a compound that destroys myeloid cells. The treatment boosted the numbers of CD8+ T cells in the blood, liver, and lymph nodes, and restored immunotherapy's effectiveness. By culturing myeloid cells with CD8+ T cells, the scientists discovered that T cells undergo apoptosis when the two types of cells come into contact.

These findings suggest that liver metastases reduce the potency of checkpoint inhibitors by drawing CD8+ T cells into the liver, where macrophages trigger the death of tumor-targeting cells. Because radiation boosts antitumor immunity, the researchers tested whether it could counteract the effect. In mice with liver metastases, radiation reduced myeloid cells in the liver and increased the effectiveness of immunotherapy.

The study indicates that “the hepatic tumor environment regulates the whole immune system,” says co-author Michael Green, MD, PhD, of the University of Michigan, Ann Arbor. He and his colleagues plan to launch a clinical trial to determine whether the combination of radiation and immune checkpoint inhibitors is beneficial for patients with liver metastases. With 25% of patients developing these metastases, “it needs to be tested in patients—and it needs to be tested now,” he says.

James Lee, MD, of the University of California, San Francisco, who was not involved in the study, lauds it for discovering “unexpected new biology of cancer immunotherapy resistance.” He agrees that clinical trials should be launched as soon as possible.

“This is a very good start,” says Brent Hanks, MD, PhD, of the Duke University School of Medicine in Durham, NC, who also wasn't connected to the study. However, timing could be a major obstacle for treatments that target hepatic metastases, he says: “Early therapy may be needed to reverse immune evasion.” –Mitch Leslie