Amazing stuff! Cancer is history (soon)!
"Humans are much more likely to get cancer than chimpanzees, despite our genomes being 98% identical. A small, genetic difference in a cell-death regulator protein called Fas Ligand, which makes human Fas Ligand more prone for degradation, could explain this vulnerability. This specific increased susceptibility could also be the reason for reduced response to some types of immunotherapy where Fas Ligand activity is relevant."
From the abstract:
"Despite sharing >98% genomic similarity, humans are more likely to develop cancers than our closest living ancestors, the nonhuman primates.
Here, we unexpectedly discover that, unlike chimpanzee and other primates, a critical embryonic development, immune homeostasis, and general cell-death regulator protein called Fas Ligand (FasL) contains a Pro153-Ser153 evolutionary substitution in humans.
The latter renders human FasL preferentially susceptible to cleavage by plasmin, an overly elevated protease in solid tumors. Since FasL-mediated killing of tumor cells by activated T-lymphocytes and chimeric antigen receptor T-cells (CAR-T) is critical for therapeutic efficacy, we find that elevated plasmin levels in certain ovarian tumors interfere with the T-lymphocyte-expressed FasL death signaling. Either targeted inhibition or blocking plasmin accessibility to membrane FasL rescues the FasL cell-death function of activated T-lymphocytes in response to immune-checkpoint receptor targeting antibodies. These findings of evolutionary significance highlight that elevated plasmin in metastatic tumors potentially contributes to differential outcomes of T-cell-based immunotherapies in solid tumors."
Evolutionary regulation of human Fas ligand (CD95L) by plasmin in solid cancer immunotherapy (open access)
Fig. 1: Proline to serine substitution at position 153 in HuFasL.
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