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

Brice E. N. Wamba, Tanmoy Mondal, Francis Freenor V, Mehr Shaheed, Oliver Pang, Daniel Bedinger, Patrick Legembre, Laurent Devel, Sanchita Bhatnagar, Gary Scott Leiserowitz and Jogender Tushir-Singh ()
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Brice E. N. Wamba: University of California Davis
Tanmoy Mondal: University of California Davis
Francis Freenor V: University of California Davis
Mehr Shaheed: University of California Davis
Oliver Pang: University of California Davis
Daniel Bedinger: Carterra
Patrick Legembre: University of Limoges
Laurent Devel: Université Paris-Saclay
Sanchita Bhatnagar: University of California Davis
Gary Scott Leiserowitz: University of California Davis
Jogender Tushir-Singh: University of California Davis

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60990-0

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