van Houtum Eline Jh, Valk Anne Hc, Granado Daniel, Lok Jasper, van den Bogaard Lune, Remkes Naomi, van Eck van der Sluijs Jesper, Span Paul N, Cornelissen Lenneke Am, Adema Gosse J
Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology Radboud University Medical Center Nijmegen The Netherlands.
Clin Transl Immunology. 2024 Sep 6;13(9):e1524. doi: 10.1002/cti2.1524. eCollection 2024 Sep.
PD-1/PD-L1 immune checkpoint blockade can be an effective treatment for advanced breast cancer patients. However, patients with oestrogen receptor positive (ER+) tumors often display only low lymphocyte infiltration, while a large part of triple negative (TN) breast tumors does not generate an effective immunotherapy response. Therefore, new treatment strategies have to be developed. Here, we investigate Siglec-7 and Siglec-9 as novel ITIM-bearing inhibitory immune checkpoint receptors similar to PD-1, but expressed on a broader range of immune cells.
We assessed Siglec-7 and Siglec-9 (ligand) expression in TN and ER+ breast cancer tumors and their breast cancer cell line-induced signalling.
We report that Siglec-7 and Siglec-9 are highly expressed in TN tumors, and to a low extent in ER+ tumors. Siglec-7 was observed on myeloid cells, T cells, and NK cells and Siglec-9 preferentially on myeloid cells. Expression of sialoglycans, including Siglec-7 and Siglec-9 ligands, was observed in both TN and ER+ breast cancer tissue sections. Expression levels of Siglec-7 and Siglec-9 ligands were higher on cultured TN cell lines than ER+ cell lines. Importantly, by applying chimeric Siglec-7 reporter cells, we showed the induction of Siglec-7 signalling by multiple TN cell lines, but only by one ER+ cell line. Moreover, Siglec-7 signalling is directly related to Siglec-7 ligand expression levels of breast cancer cell lines.
These data imply that immunotherapy targeting Siglec receptors may be particularly interesting for TN breast cancer patients not responding to current treatment strategies with tumors displaying high immune cell infiltration.
程序性死亡受体1（PD-1）/程序性死亡配体1（PD-L1）免疫检查点阻断可有效治疗晚期乳腺癌患者。然而，雌激素受体阳性（ER+）肿瘤患者的淋巴细胞浸润通常较低，而大部分三阴性（TN）乳腺癌肿瘤对免疫治疗无有效反应。因此，必须开发新的治疗策略。在此，我们研究唾液酸结合免疫球蛋白样凝集素7（Siglec-7）和唾液酸结合免疫球蛋白样凝集素9（Siglec-9），它们是类似于PD-1的新型含免疫受体酪氨酸抑制基序（ITIM）的抑制性免疫检查点受体，但在更广泛的免疫细胞上表达。
我们评估了Siglec-7和Siglec-9（配体）在TN和ER+乳腺癌肿瘤中的表达及其在乳腺癌细胞系诱导的信号传导。
我们报告Siglec-7和Siglec-9在TN肿瘤中高表达，而在ER+肿瘤中低表达。在髓样细胞、T细胞和自然杀伤（NK）细胞上观察到Siglec-7，而Siglec-9优先在髓样细胞上表达。在TN和ER+乳腺癌组织切片中均观察到唾液酸聚糖的表达，包括Siglec-7和Siglec-9配体。培养的TN细胞系上Siglec-7和Siglec-9配体的表达水平高于ER+细胞系。重要的是，通过应用嵌合Siglec-7报告细胞，我们发现多个TN细胞系可诱导Siglec-7信号传导，但只有一个ER+细胞系可以。此外，Siglec-7信号传导与乳腺癌细胞系的Siglec-7配体表达水平直接相关。
这些数据表明，对于对当前治疗策略无反应且肿瘤显示高免疫细胞浸润的TN乳腺癌患者，靶向Siglec受体的免疫治疗可能特别有意义。
