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Mutations Linked to Immunotherapy Resistance

, by NCI Staff

An oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response.

Credit: National Cancer Institute

For many patients with melanoma whose tumors shrink after treatment with a class of immunotherapy drugs called checkpoint inhibitors, their tumors eventually grow back despite continued treatment. A new study has identified genetic mechanisms that may be responsible for this acquired treatment resistance in at least some of these patients.

The researchers found mutations in tumors from three patients with advanced melanoma that allowed the tumors to become resistant to the immune checkpoint inhibitor pembrolizumab (Keytruda®). Specifically, the mutations enabled the tumors to avoid recognition and attack by immune cells.

The results, reported July 13 in The New England Journal of Medicine, are of "significant interest" because checkpoint inhibitors are now used to treat several kinds of cancer, said James Gulley, M.D., Ph.D., chief of the Genitourinary Malignancy Branch in NCI’s Center for Cancer Research.

Understanding how tumors acquire resistance to checkpoint inhibitors is critical, the study authors wrote, and may help guide the development of targeted therapies that could counteract resistance.

Immune Checkpoints

The immune system includes several so called checkpoint proteins that keep immune responses from becoming too strong. For example, binding of the protein PD-1 on T cells to the protein PD-L1 or PD-L2 on other cells suppresses the immune response. Cancer cells and cells in the environment surrounding a tumor sometimes express PD-L1, preventing immune attack.

Several immune checkpoint inhibitors target PD-1 or PD-L1, preventing them from binding and thereby allowing the immune system to attack tumor cells. Inhibitors of PD-1 and PD-L1 have been approved by the Food and Drug Administration to treat several cancer types. Pembrolizumab is a PD-1 inhibitor that is approved to treat some patients with advanced melanoma and advanced lung cancer.

Although treatment with PD-1 inhibitors causes tumors to shrink (or disappear entirely) in approximately one-third of patients with advanced melanoma, the tumor grows back (or relapses) despite continued treatment in up to one-quarter of these patients.

To investigate how tumor resistance to PD-1 inhibitors arises, Antoni Ribas, M.D., Ph.D., of the UCLA Jonsson Comprehensive Cancer Center and his colleagues sequenced the DNA of tumors from four patients with metastatic melanoma who initially responded to pembrolizumab but then relapsed after 1 to 2 years of treatment. For each patient, they compared mutations in tumor biopsies taken before treatment and after relapse to identify alterations that were acquired after treatment and may have contributed to treatment resistance.

In all four patients, more than 90% of mutations were found in both biopsies, which allowed the research team to focus on the few mutations that were unique to the relapsed tumors, explained the study’s first author, Jesse Zaretsky, an M.D.–Ph.D. student in the UCLA-Caltech Medical Scientist Training Program.

Mechanisms of Resistance

Immune checkpoint inhibitors "release the brakes" on the immune system, allowing T cells to become active and secrete a cytokine called interferon gamma. Interferon gamma suppresses the growth of cancer cells through a signaling pathway that requires JAK proteins.

Two of the four patients studied had mutations in either JAK1 or JAK2, the genes that code for JAK proteins, in their relapsed tumors. In both cases the mutation generated a shortened, nonfunctional protein.

Using cell lines from the patient who acquired a JAK2 mutation, the researchers found that the mutated JAK2 protein disrupted the interferon gamma signaling pathway. These cells also had reduced expression of genes whose products allow T cells to recognize and eliminate cancer cells.

The authors also found that interferon gamma did not inhibit growth of the JAK2-mutant tumor-derived cells or melanoma cells lines that lacked either JAK1 or JAK2.

“This may not be the only mechanism of resistance,” Dr. Gulley said, but “this is one additional piece of the puzzle of how we could overcome resistance to checkpoint inhibitors.”

Genetic analysis of biopsies from the third patient revealed a mutation in the B2M gene in the relapsed tumor. B2M helps cells express proteins on the cell surface that immune cells use to recognize and eliminate cancer cells. Acquired B2M mutations have been shown in other studies to promote tumor resistance to immunotherapy, Zaretsky explained, and these new findings appear to confirm the earlier research.

Thus, the researchers concluded that mutations in JAK1, JAK2, and B2M promote resistance to pembrolizumab by allowing tumor cells to avoid recognition and attack by immune cells.

The researchers did not identify any genetic abnormalities related to PD-1 inhibitor resistance in the fourth patient, suggesting that the relapsed tumor may have acquired resistance through a nongenetic mechanism. “Case four is a true mystery,” said Zaretsky.

Learning More

The research team is now building on this research to find ways of overcoming checkpoint inhibitor resistance.

"We’re starting to model these mutations in cell lines and mouse models so we can study their interaction with the immune system and begin testing other therapies, or combinations of therapies with PD-1 inhibitors, to try and overcome the resistance," Zaretsky said.

Because the findings only reflect mechanisms of PD-1 inhibitor resistance in four patients, additional studies will be needed to determine how prevalent these mechanisms are in other melanoma patients, said Dr. Gulley.

"We don’t know if these identified mutations will represent 80% of patients that develop resistance or 10%, but what we do know is that resistance to immune cell recognition or killing is at least one mechanism."

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