Potential melanoma target bypasses therapeutic resistance to immune checkpoint blockers (Ruxolitinib (Jakafi) helps)

Medical Xpress / Nature Communications ^ | Sept. 19, 2022 | Hongxing Shen et al

[ConservativeMind]

Immune checkpoint blockers, or ICBs, have revolutionized treatment for various cancers. However, three-fourths of advanced-melanoma patients are resistant to ICBs.

Now, researchers reveal a potential target—using the clinically approved drug ruxolitinib—to suppress ICB-resistant melanomas.

"Since ruxolitinib is clinically approved and being tested in patients with advanced solid tumors, non-small-cell lung cancer and triple-negative breast cancer, our study justifies further testing of ruxolitinib in patients with advanced melanoma that are resistant to ICBs," said Lewis Zhichang Shi, M.D., Ph.D.

It was known that tumor loss of interferon-gamma signaling was a major mechanism of resistance against two ICB drugs, anti-CTLA-4 and anti-PD-1. However, ways to overcome this resistance remained elusive.

This loss of interferon-gamma signaling in human melanomas is caused by dysregulation of genes. However, in mouse models the knockdown mutations failed to show how a loss of interferon-gamma signaling in tumor cells modulated the activity of tumor-infiltrating T cells, or TILs.

So researchers created a cleaner mouse melanoma model by knocking out the receptor gene for interferon-gamma signaling. They used this improved knockout model—called IFNγR1KO—to probe the mechanisms of ICB resistance and how the IFNγR1KO melanomas alter the response of TILs to ICBs.

This revealed that normal interferon-gamma signaling in the melanoma plays an important role in shaping TILs.

Mechanistically, the IFNγR1KO mouse melanomas had a network of continuously active protein tyrosine kinases that centered on activated JAK1/2 kinases.

Ruxolitinib is an inhibitor of JAK1/2. The researchers found that ruxolitinib suppressed the cancerous growth of IFNγR1KO melanomas, but not control melanomas. Experimental depletion of T cells or host tumor necrosis factor signaling completely abrogated ruxolitinib efficacy, leading researchers to conclude that ruxolitinib suppression of the IFNγR1KO melanomas depends on T cells and the host cytokine tumor necrosis factor. Researchers also found that ruxolitinib mediates its therapeutic effect by reprogramming the TILs.

[ConservativeMind]

For it to work, you need to not take anything that lessens Tumor Necrosis Factor, so antioxidants are not good, should you need to take ruxolitinib.

[ConservativeMind]

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[xkaydet65]

9 years too late for my wife. Yervoy didn’t help. Though Opdivomay have with the Yervoy. But it wasn’t available then.carter got the duo the next year and his melanoma had the exact same manifestations as my wife’s. As she would say, And so it goes. Here’s hoping this new one works because Melanoma is evil.