Why Melanoma Tumors Need to be “Hot” for Immunotherapy Treatments

Why Melanoma Tumors Need to be “Hot” for Immunotherapy Treatments


melanomaMelanoma tumors are usually classified as either “hot” or “cold.” When they’re hot, immunotherapy makes the tumors extremely visible to the immune system. But nearly 50% of the tumors are cold, which means the immune system can’t see them, and they rarely respond to immunotherapy treatments. Until now, researchers have not been able to determine a “hot” melanoma from a “cold” one, so doctors have simply been administering immunotherapy treatments and crossing their fingers. But a new study recently discovered a possible way to predict the “temperature” of melanomas.


immunotherapyThe study, performed by a team at the University of Colorado Cancer Center, revealed that tumors with gene mutations creating an overreaction of the NF-kB signaling pathway were 3 times more likely to respond to anti-PD1 checkpoint inhibitor drugs compared with tumors that did not undergo those changes. According to Carol Amato, MS, investigator at CU Cancer Center, the team is “pretty close to pinpointing high NF-kB as a predictor of response.” 


One hypothesis about what makes a tumor “hot” is its tumor mutation burden (TMB), or the number of mutations a tumor has. In theory, the more mutations a tumor has, the more distinguished it would be from healthy tissue, which would give it a greater chance of being recognized and attacked by the immune system. 

But Amato and her team believe more specific and significant changes are responsible for the immune system’s ability to see tumor tissue. Their study was intent on discovering what exactly those changes are.

In order to do so, they took a look at 400 patient samples gathered over the past ten years by the Robinson lab in the Colorado Skin Cancer Biorepository. “In this project,” said Amato, “we asked which of these 400 patients had been treated with immunotherapy, and whether genetic or genomic features of their tumors could predict response to treatment.” 

They found that of 52 patients who received anti-PD1 immunotherapies, 21 responded well to them and 31 showed little or no response. Sixty-seven percent of those who responded well had gene alterations associated with the NF-kB signaling pathway. This was compared with only 19 percent in those whose tumors did not show any response to the immunotherapy. 

However, the NF-kB pathway is particularly complex. Overactive Nf-kB signaling has actually been identified as a cause for the development of many different cancers. But that same overactive signaling could also give immunotherapies a better chance at targeting cancers that already exist.

One of the reasons this pathway is so complex is because of a particular mutation in NFKBIE, which is a negative regulator of KF-kB. The mutation is called G34E, and its found only in the tumors that did respond to immunotherapy. It functions by removing a limiter on NF-kB, which then created increased activation of the pathway. When it was over activated, the transcription factor NF-kB passed into the cell nucleus and magnified the expression of the gene CD83. 



Amato and her team think that CD83 is “enhancing the responsiveness of the tumor to immunotherapy” by showing antigens on the surface of tumor cells that allow the immune system to see it. When the team artificially increased NFKBIE G34E mutations, there was an increase in NF-kB signaling, and that action was separate from many of the genetic changes commonly associated in melanoma. 



Even beyond tumor mutation burden,” said Amato, “these specific changes could help doctors predict which melanoma patients will respond and which patients will not respond to anti-PD1 immunotherapies.”