[ad_1]
Melanomas tend to be "hot" or "cold – if they are hot, immunotherapy turns on melanomas as beacons intended to be eliminated by the immune system. But 40% to 50% of melanomas are cold, making them invisible to the immune system. and patients with cold tumors tend to show that immunotherapies provide little benefit.
The problem is that it was impossible to distinguish a hot melanoma from a cold melanoma. The solution was to administer immunotherapy and hope that everything would be fine, often leading to loss of time and resources. A study from the University of Colorado Cancer Center presented at the 2019 annual meeting of the American Association for Cancer Research (AACR) identifies a possible way to predict which melanomas are hot and cold: Tumors with mutations in genes leading to overactivation of the NF-κB signaling pathway were more than three times more likely to respond to anti-PD-1 immunotherapy compared to tumors in which these changes were absent.
"I would like to deepen the examination a bit, but we are on the verge of determining whether a high NF-κB level is a predictor of the response," said Carol Amato, MS, a researcher at the Canadian Cancer Center. CU and Senior Professional Research Assistant.
One of the factors thought to create a "hot" tumor is the overall burden of tumor mutation – the total number of mutations in a tumor – the idea being that more mutations would create more differences between the tumor and the tissue healthy, which would increase the likelihood that the immune system will recognize the tumor tissue as foreign and will strive to eliminate it.
However, Amato and his colleagues, including William Robinson, MD, PhD, and first author, Keith Wells, MD, show that while the overall burden of tumor mutation can increase the risk of significant genetic changes, the immune system's capacity to see the tumor tissue may depend more on specific factors. , significant changes in the overall burden of change.
To discover what these changes are, the group exploited patient samples collected during the decade by the Robinson lab in Colorado's bio-exposure on skin cancer. "Basically, a few years ago, we decided to perform a complete exome sequencing on our sample of 500 melanoma samples, or about 500 melanoma samples." In this project, we asked what patients had been treated with immunotherapy, and whether genetic or genomic characteristics of their tumors could predict the response to treatment, "says Amato.
Of 52 patients treated with PD-1 immunotherapy, 21 responded favorably and 31 had low or no benefit. Sixty-seven percent of those who responded favorably had gene alterations badociated with the NF-kB signaling pathway, compared to only 19% in patients whose tumors had failed to respond to immunotherapy. "NF-kB is a complex pathway, sometimes it is bad and sometimes it is good, and the context of the cell may be different from that of the treatment," says Amato.
What it does mean is that, on the one hand, too active NF-kB signaling has been implicated in the development of many cancers ("sometimes, it's serious") ). On the other hand, too active NF-kB signaling may also allow immunotherapies to better target existing cancers ("sometimes it's good"). "What we are showing is that cancers with alterations that overactivate NF-kB could better benefit from immunotherapy," says Amato.
The exact reason for this is the case is complex and requires looking inside the NF-kB signaling pathway leading to a specific mutation in NFKBIE, a negative regulator of NF-kB. This mutation, G34E, found only in tumors that responded to immunotherapy, has an effect similar to that of the elimination of a limiter on NF-kB, allowing increased activation of this pathway. Then, when it was specifically activated, the NF-κB transcription factor could pbad into the nucleus of the cell, where it amplified CD83 gene expression.
"And we think it's the CD83 that enhances the tumor's responsiveness to immunotherapy," Amato explains, explaining this action by suggesting that CD83 might present antigens on the surface of tumor cells, which which makes them more visible to the immune system. When the group artificially increased NFKBIE G34E mutations, it found an increase in NF-kB signaling. And this activity was independent of many genetic modifications commonly observed in melanomas, for example: BRAF and NRAS mutations.
"Even beyond the burden of tumor mutation, these specific changes could help doctors predict which melanoma patients will respond and which patients will not respond to anti-PD-1 immunotherapies," said Amato.
To read more, click here.
Source link
