Sialyl-tn in cancer: (how) did we miss the target?

Abstract

Sialyl-Tn antigen (STn) is a short O-glycan containing a sialic acid residue a2,6-linked to GalNAca-O-Ser/Thr. The biosynthesis of STn is mediated by a specific sialyltransferase termed ST6GalNAc I, which competes with O-glycans elongating glycosyltransferases and prevents cancer cells from exhibiting longer O-glycans. While weakly expressed by fetal and normal adult tissues, STn is expressed by more than 80% of human carcinomas and in all cases, STn detection is associated with adverse outcome and decreased overall survival for the patients. Because of its pan-carcinoma expression associated with an adverse outcome, an anti-cancer vaccine, named Theratope, has been designed towards the STn epitope. In spite of the great enthusiasm around this immunotherapy, Theratope failed on Phase III clinical trial. However, in lieu of missing this target, one should consider to revise the Theratope design and the actual facts. In this review, we highlight the many lessons that can be learned from this failure from the immunological standpoint, as well as from the drug design and formulation and patient selection. Moreover, an irrefutable knowledge is arising from novel immunotherapies targeting other carbohydrate antigens and STn carrier proteins, such as MUC1, that will warrantee the future development of more successful anti-STn immunotherapy strategies.

Figure 1

The initial steps of the O-glycan biosynthesis showing cores and sialyl-Tn (STn) competition for the initial GalNAc.

Figure 2

STn frequency in the most studied cancers. Each dot represents a report (see Figure 3 for references). The red bar is the mean of the percentage of STn positive cases.

Figure 3

STn frequency in various carcinomas. The diagram shows the percentage of STn positive cases detected in various carcinomas using different anti-STn mAbs. The average percentage of positive cases is indicated below the type of cancer. The numbers on the top of the bars indicate the number of samples used for each study. References are indicated at the base of each bar, including [56,57,58,59,60,61,62] that are not quoted elsewhere in the text. SCC: Squamous cell carcinoma, AC: adenocarcinoma.

Figure 4

Graphic overview of STn expression in cancers. The picture represents the published papers reviewed herein sorted by cancer type. Top part: reports of positive (blue) or negative (white) expression in various tissues and cancer. For first and second lines, positive expression relates to a sparse and low expression as described in Section 3.2.1. and Section 3.2.2. In colorectal cancer, O-acetylated STn is considered to be a positive report since it requires the activity of ST6GalNAc I (see Chapter 2.). The forth line summarizes Figure 2 and Figure 3. Bottom part: reports assessing the correlation between STn expression and clinical features of cancers, with a significant correlation found in pink and no correlation found in white. Size of the circles represents the number of published reports (diameter calculated as 1 + 0.1 unit per publication).

Figure 5

Simplified depiction of tumor antigen recognition and the induction of humoral immune responses. Tumor antigens can be directly recognized by B cells, and the cross-linking of the B cell receptors leads to IgM secretion through T cell-independent B cell activation. Tumor antigens can be endocytosed by antigen presenting cells, such as DCs and then presented to Th cells, thus leading to T cell activation and subsequent T cell-dependent B cell activation.

Figure 6

Age-specific (crude) SEER incidence rate by cancer sites. All ages, all races, 1992-2009.