British Journal of Cancer ( IF 8.8 ) Pub Date : 2021-09-15 , DOI: 10.1038/s41416-021-01530-7 Troels Boldt Rømer 1 , Mikkel Koed Møller Aasted 1 , Sally Dabelsteen 2 , Aaron Groen 3 , Julia Schnabel 3 , Edwin Tan 3 , Johannes Wirenfeldt Pedersen 1 , Amalie Dahl Haue 1 , Hans Heugh Wandall 1
Background
Novel immunotherapies targeting cancer-associated truncated O-glycans Tn (GalNAcα-Ser/Thr) and STn (Neu5Acα2–6GalNacα-Ser/Thr) are promising strategies for cancer treatment. However, no comprehensive, antibody-based mapping of truncated O-glycans in tumours exist to guide drug development.
Methods
We used monoclonal antibodies to map the expression of truncated O-glycans in >700 tissue cores representing healthy and tumour tissues originating from breast, colon, lung, pancreas, skin, CNS and mesenchymal tissue. Patient-derived xenografts were used to evaluate Tn expression upon tumour engraftment.
Results
The Tn-antigen was highly expressed in breast (57%, n = 64), colorectal (51%, n = 140) and pancreatic (53%, n = 108) tumours, while STn was mainly observed in colorectal (80%, n = 140) and pancreatic (56%, n = 108) tumours. We observed no truncated O-glycans in mesenchymal tumours (n = 32) and low expression of Tn (5%, n = 87) and STn (1%, n = 75) in CNS tumours. No Tn-antigen was found in normal tissue (n = 124) while STn was occasionally observed in healthy gastrointestinal tissue. Surface expression of Tn-antigen was identified across several cancers. Tn and STn expression decreased with tumour grade, but not with cancer stage. Numerous xenografts maintained Tn expression.
Conclusions
Surface expression of truncated O-glycans is limited to cancers of epithelial origin, making Tn and STn attractive immunological targets in the treatment of human carcinomas.
中文翻译:
上皮和非上皮来源癌症中截短 O-聚糖的定位
背景
针对癌症相关的截短 O-聚糖 Tn (GalNAcα-Ser/Thr) 和 STn (Neu5Acα2–6GalNacα-Ser/Thr) 的新型免疫疗法是癌症治疗的有前景的策略。然而,目前还没有全面的、基于抗体的肿瘤中截短 O-聚糖的图谱来指导药物开发。
方法
我们使用单克隆抗体来绘制 > 700 个组织核心中截短的 O-聚糖的表达图,这些组织核心代表源自乳房、结肠、肺、胰腺、皮肤、CNS 和间充质组织的健康和肿瘤组织。患者来源的异种移植物用于评估肿瘤移植后的 Tn 表达。
结果
Tn 抗原在乳腺(57%,n = 64)、结直肠(51%,n = 140)和胰腺(53%,n = 108)肿瘤中高表达,而 STn 主要在结直肠(80%,n = 140) 和胰腺 (56%, n = 108) 肿瘤。我们观察到间充质肿瘤 ( n = 32)中没有截短的 O-聚糖和 CNS 肿瘤中 Tn (5%, n = 87) 和 STn (1%, n = 75) 的低表达。在正常组织中未发现 Tn 抗原(n = 124),而 STn 偶尔会在健康的胃肠道组织中观察到。在几种癌症中鉴定了 Tn 抗原的表面表达。Tn 和 STn 表达随肿瘤分级而下降,但不随癌症分期而下降。许多异种移植物维持了 Tn 表达。
结论
截短的 O-聚糖的表面表达仅限于上皮来源的癌症,这使得 Tn 和 STn 在人类癌症治疗中具有吸引力的免疫靶点。