How Melanoma Tumors Fight Immunotherapy Revealed

Melanoma tumors are able to resist the immunotherapy ipilimumab (Yervoy) using interferon-gamma (IFN-y) mutations in a prominent immune response pathway.

Yervoy was approved by the FDA in 2011 for the treatment of metastatic melanoma. It was the first drug to unleash an immune attack on cancer by blocking the protein CTLA-4 that acts as a brake on T cells. In a new study published in Cell, researchers were able to clearly identify for the first time the resistance pathway to Yervoy.

The findings create a doorway for testing a range of IFN-y genes prospectively as a predictor for Yervoy response, and for exploring new combinations that could defeat IFN-y-related resistance.

“Research has shown that ipilimumab [Yervoy] treatment provides a significant survival benefit in about 20% of patients with melanoma,” said study leader Padmanee Sharma, MD, PhD. “The mechanisms responsible for the lack of clinical response in the majority of patients have remained unknown.”

Normally, IFN-y is an immune response-stimulating cytokine that can directly attack tumor cells by connecting to receptors on the cell surface, which sets off a chain of events that inhibits cell growth and promotes tumor cell death, according to Sharma. However, researchers believe the direct cell-killing role may be blocked by genetic mutations.

Prior research conducted by these study authors have shown that treatment with Yervoy resulted in increased production of IFN-y by T cells. From these findings, researchers hypothesized that defective tumor cells in the IFN-y pathway may resist Yervoy treatment.

To test their theory, researchers evaluated the whole exome gene sequencing data for IFN-y pathway genes in the tumors of 16 melanoma patients treated with Yervoy. Only 4 out of the 16 participants responded to treatment.

In the tumors of 12 patients who were non-responders, a total of 184 mutations were detected, including 142 with copy number alterations and 42 with single nucleotide variants. In the tumors of the responders, only 4 mutations were found.

Non-responders have an average of 15.33 mutations in IFN-y pathway genes, with copy number variations accounting for the significant difference. Of the 12 non-responders, 9 had copy number alterations.

The most significant included genomic loss of the 2 receptors for IFN-y, IFNGR1, and 2 important downstream genes called IRF-1 and JAK2. Additionally, 2 known inhibitors of the pathway, called SOCS1 and PIAS4, were amplified.

Researchers conducted an analysis of the survival data of 367 melanoma patients in The Cancer Genome Atlas database. They found that patients with copy number alterations had significantly shorter survival of 40 months, compared with 48.2 months for patients without the mutations.

In a melanoma cell line vulnerable to IFN-y attack, researchers found that by knocking out IFNGR1 it allowed for the tumor cells to grow, even in the presence of IFN-y.

When researchers used the small cell line B16/BL6 in mice treated with Yervoy, they found that only 4 of 24 mice with an intact IFN-y receptor developed cancer. In the 25 mice that had the receptor knocked down, 12 developed tumors.

All of the untreated mice died from tumor growth, while 80% of mice with intact IFN-y receptors treated with Yervoy survived, compared with approximately half of mice who had the receptor knocked out.

The findings suggest the potential use of an 11-gene IFN-y pathway signature that can be tested in prospective clinical trials as a predictor of response to Yervoy. If it is confirmed, it can be used to guide Yervoy treatment either alone, or in combination with other drugs.

Authors noted that an additional area to explore is finding combination therapies that overcome the loss of the IFN-y pathway.

“We might be able to stimulate the immune system to produce other cytokines that can overcome tumors with IFN-y pathway genes turned off,” Sharma said.

Sharma also noted that although IFN-y is important, it is likely that there are other mechanisms in tumors that help them resist immunotherapy.