Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer
© 2023. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Cell death and differentiation - 30(2023), 11 vom: 11. Nov., Seite 2408-2431 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mondal, Tanmoy [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies |
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| Anmerkungen: |
Date Completed 20.11.2023 Date Revised 20.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41418-023-01229-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363317317 |
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| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Gaur, Himanshu |e verfasserin |4 aut | |
| 700 | 1 | |a Wamba, Brice E N |e verfasserin |4 aut | |
| 700 | 1 | |a Michalak, Abby Grace |e verfasserin |4 aut | |
| 700 | 1 | |a Stout, Camryn |e verfasserin |4 aut | |
| 700 | 1 | |a Watson, Matthew R |e verfasserin |4 aut | |
| 700 | 1 | |a Aleixo, Sophia L |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Arjun |e verfasserin |4 aut | |
| 700 | 1 | |a Condello, Salvatore |e verfasserin |4 aut | |
| 700 | 1 | |a Faller, Roland |e verfasserin |4 aut | |
| 700 | 1 | |a Leiserowitz, Gary Scott |e verfasserin |4 aut | |
| 700 | 1 | |a Bhatnagar, Sanchita |e verfasserin |4 aut | |
| 700 | 1 | |a Tushir-Singh, Jogender |e verfasserin |4 aut | |
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