Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer.
Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer.
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DOI：
10.1038/s41418-023-01229-7
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发表时间：
2023-11
影响因子：
12.4
通讯作者：
Tushir-Singh, Jogender
中科院分区：
文献类型：
--
作者：
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
受体聚集是TNF超家族死亡受体激活外源性凋亡的最关键步骤。尽管使用激动剂抗体在临床上不成功，但从癌症治疗学的角度来看，死亡受体-5仍然被广泛研究。然而，尽管其在卵巢和其他实体瘤中的调节作用和功能提高，但另一种称为Fas（CD 95）的肿瘤富集死亡受体在癌症免疫治疗中仍然被低估，直到最近，它在CAR-T疗法的脱靶肿瘤杀伤中的作用才成为当务之急。通过全面分析的背景下的FasL和各种临床前Fas激动剂抗体的结合表位的结构研究，我们表征了一个高度显着的补丁的正电荷残基表位（PPCR）在其富含半胱氨酸的结构域2的Fas。PPCR参与对于卵巢肿瘤模型中的上级Fas激动剂信号传导和CAR-T旁观者功能是必不可少的。干扰PPCR参与的FasL或Fas的单点突变抑制肿瘤细胞和T细胞中的凋亡信号传导。此外，考虑到自身免疫性淋巴组织增生综合征（ALPS）的临床和免疫学特征直接归因于FasL的纯合突变，我们揭示了与所述ALPS突变相比，PPCR界面处的FasL/Fas聚类的差异机制细节。由于Fas介导的旁观者杀伤对于肿瘤中CAR-T疗法的成功仍然至关重要，我们的研究结果强调了使用死亡激动剂改善卵巢和其他实体瘤中癌症免疫治疗的潜在有效Fas靶向策略的治疗分析设计。
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.
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DOI：
10.1007/978-1-62703-640-5_12
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Wollebo, Hassen S;Woldemichaele, Baheru;White, Martyn K
通讯作者：
White, Martyn K
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.6
作者：
Ceppi, Paolo;Hadji, Abbas;Kohlhapp, Frederick J.;Pattanayak, Abhinandan;Hau, Annika;Liu, Xia;Liu, Huiping;Murmann, Andrea E.;Peter, Marcus E.
通讯作者：
Peter, Marcus E.
影响因子：
7.2
作者：
Annibaldi, Alessandro;Walczak, Henning
通讯作者：
Walczak, Henning
影响因子：
20.3
作者：
Del-Rey, Manuel;Ruiz-Contreras, Jesus;Allende, Luis M.
通讯作者：
Allende, Luis M.