Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer

Receptor clustering is the most critical step to activate extrinsic apoptosis by death receptors belonging to the TNF superfamily. Although clinically unsuccessful, using agonist antibodies, the death receptors-5 remains extensively studied from a cancer therapeutics perspective. However, despite it...

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Published in:	Cell death and differentiation Vol. 30; no. 11; pp. 2408 - 2431
Main Authors:	Mondal, Tanmoy, Gaur, Himanshu, Wamba, Brice E. N., Michalak, Abby Grace, Stout, Camryn, Watson, Matthew R., Aleixo, Sophia L., Singh, Arjun, Condello, Salvatore, Faller, Roland, Leiserowitz, Gary Scott, Bhatnagar, Sanchita, Tushir-Singh, Jogender
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-11-2023 Nature Publishing Group
Subjects:	101/1 13/106 13/109 13/2 631/67/2329 631/67/327 692/308/2778 82 82/1 82/16 96 96/2 96/31 Agonists Antibodies Antibodies - pharmacology Apoptosis Biochemistry Biomedical and Life Sciences Cancer immunotherapy CD95 antigen Cell Biology Cell Cycle Analysis Death receptors Epitopes Fas Ligand Protein fas Receptor - genetics fas Receptor - metabolism FasL protein Female Humans Immunotherapy Life Sciences Lymphocytes Lymphocytes T Mutation Ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - therapy Point mutation Receptor density Receptors, Chimeric Antigen Solid tumors Stem Cells T-Lymphocytes Tumor cells Tumors
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Summary:	Receptor clustering is the most critical step to activate extrinsic apoptosis by death receptors belonging to the TNF superfamily. Although clinically unsuccessful, using agonist antibodies, the death receptors-5 remains extensively studied from a cancer therapeutics perspective. However, despite its regulatory role and elevated function in ovarian and other solid tumors, another tumor-enriched death receptor called Fas (CD95) remained undervalued in cancer immunotherapy until recently, when its role in off-target tumor killing by CAR-T therapies was imperative. By comprehensively analyzing structure studies in the context of the binding epitope of FasL and various preclinical Fas agonist antibodies, we characterize a highly significant patch of positively charged residue epitope (PPCR) in its cysteine-rich domain 2 of Fas. PPCR engagement is indispensable for superior Fas agonist signaling and CAR-T bystander function in ovarian tumor models. A single-point mutation in FasL or Fas that interferes with the PPCR engagement inhibited apoptotic signaling in tumor cells and T cells. Furthermore, considering that clinical and immunological features of the autoimmune lymphoproliferative syndrome (ALPS) are directly attributed to homozygous mutations in FasL, we reveal differential mechanistic details of FasL/Fas clustering at the PPCR interface compared to described ALPS mutations. As Fas-mediated bystander killing remains vital to the success of CAR-T therapies in tumors, our findings highlight the therapeutic analytical design for potentially effective Fas-targeting strategies using death agonism to improve cancer immunotherapy in ovarian and other solid tumors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1350-9047 1476-5403
DOI:	10.1038/s41418-023-01229-7