UAB Department of Radiation Oncology Chair James A. Bonner, M.D., and Associate Professor Lewis Zhichang Shi, M.D., Ph.D., recently published research with new implications for treating melanoma patients.

The article, “Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling” published in Nature Communications discusses the pressing issue of resistance to immunotherapy drugs called immune checkpoint blockers (ICBs) in melanoma patients.

Immune checkpoints are a normal part of the immune system that occur when proteins on the surface of immune cells (T cells) bind with their partner proteins on other cells such as tumor cells. This binding signals to the T cells not to destroy the cancer cells. ICBs work by blocking the binding, which allows the T cells to kill the cancer cells.

Melanoma, the most serious form of skin cancer, was largely considered incurable prior to the era of ICBs, yet accumulative data show only a subset of melanoma patients actually benefit from ICBs, limiting their clinical use.

Initial research from Dr. Shi (while working at The University of Texas MD Anderson Cancer Center with Padmanee Sharma, M.D., Ph.D., and Jim Allison, Ph.D.) on therapeutic resistance to ICBs in melanoma cells identified a lack of certain signaling genes (IFN-γ). Strategies to overcome this mechanism of resistance have remained largely unexplored until now.

Upon relocating to UAB in 2018, the Shi group, teaming up with Bonner group and other research teams within the department, set out to uncover therapeutic targets to treat ICB-resistant melanomas lacking functional IFN-γ signaling. They started by creating a new melanoma model that lacked IFN-γ signaling and was completely resistant to ICBs.

Researchers demonstrated that melanomas lacking IFN-γ signaling have reduced infiltration and effector function of tumor-infiltrating T cells (TILs) but exhibit an unusually active mTOR-JAK1/2 axis, a pathway essential for cell survival.

Their findings led them to employ Ruxolitinib (Ruxo), an FDA-approved JAK1/2 inhibitor to treat myeloproliferative neoplasms (MPN), a type of blood cancers. They found inhibiting activated JAK1/2 with Ruxo induced selective suppression of IFNγR1KO melanomas, in a precision medicine fashion.

“Since Ruxo is clinically approved, our study justifies further testing of Ruxo in patients with advanced melanoma that are resistant to ICBs, particularly those with impaired IFN-γ signaling,” Dr. Shi said. “We are actively soliciting clinical interests in exploring JAK1/2 inhibition as a strategy to overcome ICB resistance in melanoma patients, a pressing unmet medical need.”

Read the full article with results in Nature Communications.

Read Dr. Shi’s related “Behind the Paper” post, “Overcoming immunotherapy resistance in melanoma defective of IFN-g signaling” in the online Nature Portfolio Cancer Community.