Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.
Front Immunol. 2023 Jun 6;14:1178817. doi: 10.3389/fimmu.2023.1178817. eCollection 2023.
Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9. Treatment of tumor cells with neuraminidases or a sialyl transferase inhibitor significantly reduced binding of a soluble recombinant Siglec-9-Fc fusion protein, while EGFR and HER2 expression remained unchanged. Importantly, the cytotoxic activity of neutrophils driven by therapeutic EGFR or HER2 antibodies was increased by blocking the sialic acid/Siglec interaction, either by reducing tumor cell sialylation or by a Siglec-9 blocking antibody containing an effector silenced Fc domain. a short-term xenograft mouse model confirmed the improved therapeutic efficacy of EGFR antibodies against sialic acid depleted, by a sialyltransferase inhibitor, tumor cells compared to untreated cells. Our studies demonstrate that sialic acid/Siglec interactions between tumor cells and myeloid cells can impair antibody dependent tumor cell killing, and that Siglec-9 on polymorphonuclear cells (PMN) is critically involved. Considering that PMN are often a highly abundant cell population in the tumor microenvironment, Siglec-9 constitutes a promising target for myeloid checkpoint blockade to improve antibody-based tumor immunotherapy.
肿瘤细胞表面唾液酸化糖链的上调是促进肿瘤生长和进展的机制之一。具体来说,唾液酸与淋巴细胞或髓细胞上的唾液酸结合免疫球蛋白样凝集素(Siglec)的相互作用传递抑制信号,导致抗肿瘤反应受到抑制。在这里,我们表明中性粒细胞表达 Siglec-9 等,并且 EGFR 和 HER2 阳性乳腺癌肿瘤细胞表达 Siglec-9 的配体。用神经氨酸酶或唾液酸转移酶抑制剂处理肿瘤细胞可显著降低可溶性重组 Siglec-9-Fc 融合蛋白的结合,而 EGFR 和 HER2 表达保持不变。重要的是,通过阻断唾液酸/Siglec 相互作用,无论是通过减少肿瘤细胞的唾液酸化还是通过含有效应物沉默 Fc 结构域的 Siglec-9 阻断抗体,来治疗性 EGFR 或 HER2 抗体驱动的中性粒细胞的细胞毒性活性均增加。短期异种移植小鼠模型证实,与未经处理的细胞相比,用唾液酸转移酶抑制剂耗尽唾液酸的肿瘤细胞对 EGFR 抗体的治疗效果得到了改善。我们的研究表明,肿瘤细胞和髓样细胞之间的唾液酸/Siglec 相互作用会损害抗体依赖性肿瘤细胞杀伤,并且多形核细胞(PMN)上的 Siglec-9 是关键。考虑到 PMN 通常是肿瘤微环境中高度丰富的细胞群体,Siglec-9 是髓样细胞检查点阻断以改善基于抗体的肿瘤免疫治疗的有前途的靶标。