Evolutionary regulation of human Fas ligand (CD95L) by plasmin in solid cancer immunotherapy

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.