Department of Surgery, Laboratory for Translational Surgical Oncology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
Graduate School, Shantou University Medical College, Shantou, Guangdong, China.
Oncoimmunology. 2021 Nov 20;10(1):2005344. doi: 10.1080/2162402X.2021.2005344. eCollection 2021.
Cancer cells exploit CD47 overexpression to inhibit phagocytic elimination and neoantigen processing via the myeloid CD47-SIRPα axis and thereby indirectly evade adaptive T cell immunity. Here, we report on a hitherto unrecognized direct immunoinhibitory feature of cancer cell-expressed CD47. We uncovered that in response to IFNγ released during cognate T cell immune attack, cancer cells dynamically enhance CD47 cell surface expression, which coincides with acquiring adaptive immune resistance toward pro-apoptotic effector T cell mechanisms. Indeed, CRISPR/Cas9-mediated CD47-knockout rendered cancer cells more sensitive to cognate T cell immune attack. Subsequently, we developed a cancer-directed strategy to selectively overcome CD47-mediated adaptive immune resistance using bispecific antibody (bsAb) CD47xEGFR-IgG2s that was engineered to induce rapid and prolonged cancer cell surface displacement of CD47 by internalization. Treatment of CD47 cancer cells with bsAb CD47xEGFR-IgG2s potently enhanced susceptibility to cognate CD8 T cells. Targeting CD47-mediated adaptive immune resistance may open up new avenues in cancer immunotherapy.
癌细胞利用 CD47 的过度表达，通过髓系 CD47-SIRPα 轴抑制吞噬作用和新抗原加工，从而间接逃避适应性 T 细胞免疫。在这里，我们报告了一个以前未被认识到的癌细胞表达的 CD47 的直接免疫抑制特征。我们发现，在细胞毒性 T 细胞免疫攻击过程中释放的 IFNγ 的刺激下，癌细胞动态地增强 CD47 细胞表面表达，同时获得对促凋亡效应 T 细胞机制的适应性免疫抵抗。事实上，CRISPR/Cas9 介导的 CD47 基因敲除使癌细胞对细胞毒性 T 细胞免疫攻击更敏感。随后，我们开发了一种针对癌症的策略，使用双特异性抗体（bsAb）CD47xEGFR-IgG2 来选择性地克服 CD47 介导的适应性免疫抵抗，该抗体被设计为通过内化诱导 CD47 的快速和持久的癌细胞表面位移。用 bsAb CD47xEGFR-IgG2 处理 CD47 阳性癌细胞，显著增强了对同源 CD8 T 细胞的敏感性。靶向 CD47 介导的适应性免疫抵抗可能为癌症免疫治疗开辟新途径。
