Department of Bio-therapeutic, the First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.
School of Medicine, Nankai University, Tianjin, China.
Blood Adv. 2022 Nov 22;6(22):5844-5856. doi: 10.1182/bloodadvances.2022007891.
Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in treating a variety of hematologic malignancies, but resistance to this treatment in some patients limited its wider application. Using an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) screening, we identified and validated loss of CD58 conferred immune evasion from CAR T cells in vitro and in vivo. CD58 is a ligand of the T-cell costimulatory molecule CD2, and CD58 mutation or downregulated expression is common in hematological tumors. We found that disruption of CD58 in tumor cells induced the formation of suboptimal immunological synapse (IS) with CAR T cells, which conferred functional impairment of CAR T cells, including the attenuation of cell expansion, degranulation, cytokine secretion, and cytotoxicity. In summary, we describe a potential mechanism of tumor-intrinsic resistance to CAR T-cell therapy and suggest that this mechanism may be leveraged for developing therapeutic strategies to overcome resistance to CAR T-cell therapy in B-cell malignancies.
嵌合抗原受体 (CAR) T 细胞疗法在治疗多种血液系统恶性肿瘤方面取得了显著成功，但一些患者对此治疗的耐药性限制了其更广泛的应用。我们使用无偏基因组范围的成簇规律间隔短回文重复 (CRISPR)/CRISPR 相关蛋白 9 (Cas9) 筛选，在体外和体内鉴定并验证了 CD58 的缺失赋予了 CAR T 细胞的免疫逃逸能力。CD58 是 T 细胞共刺激分子 CD2 的配体，CD58 突变或下调表达在血液系统肿瘤中很常见。我们发现肿瘤细胞中 CD58 的破坏诱导了与 CAR T 细胞形成次优免疫突触 (IS)，从而导致 CAR T 细胞功能受损，包括细胞扩增、脱颗粒、细胞因子分泌和细胞毒性的减弱。总之，我们描述了肿瘤内在对 CAR T 细胞疗法产生耐药性的潜在机制，并表明可以利用该机制来开发治疗策略，以克服 B 细胞恶性肿瘤中对 CAR T 细胞疗法的耐药性。
