Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.

Mucin O-glycosylation is characterized in cancer by aberrant expression of immature carbohydrate structures (Tn, T, and sialyl-Tn antigens). The UDP-N-acetyl-d-galactosamine: polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-T) family enzymes regulate the initial steps of mucin O-glycosylation and could be responsible for the altered glycosylation observed in cancer. Considering that we recently found the ppGalNAc-T6 mRNA expressed in breast carcinomas, we produced a highly specific monoclonal antibody (MAb T6.3) to assess the expression profile of ppGalNAc-T6 protein product in breast tissues. The expression of ppGalNAc-T6 by breast carcinoma cells was confirmed on MCF-7 and T47D cell lines. In formalin-fixed tissues, ppGalNAc-T6 expression was observed in 60/74 (81%) breast cancers, 21/23 (91.3%) adjacent ductal carcinoma in situ (DCIS), 4/20 benign breast lesions (2/2 sclerosing adenosis and 2/13 fibroadenoma), and in 0/5 normal breast samples. We observed a statistically significant association of ppGalNAc-T6 expression with T1 tumor stage. This fact, as well as the observation that ppGalNAc-T6 was strongly expressed in sclerosing adenosis and in most DCIS, suggests that ppGalNAc-T6 expression could be an early event during human breast carcinogenesis. Considering that an abnormal O-glycosylation greatly contributes to the phenotype and biology of breast cancer cells, ppGalNAc-T6 expression could provide new insights about breast cancer glycobiology.

Simple mucin‐type O‐glycan structures, such as Tn, TF, sialyl‐Tn and Tk antigens, are among of the most specific human cancer‐associated structures. These antigens are involved in several types of receptor‐ligand interactions, and they are potential targets for immunotherapy. In the last few years several simple mucin‐type O‐glycan antigens were identified in different species belonging to the main two helminth parasite phyla, and sialyl‐Tn bearing glycoproteins were detected in Trypanosoma cruzi. These results are of interest to understand new aspects in parasite glycoimmunology and may help identify new biological characteristics of parasites as well of the host‐parasite relationship. Considering that different groups reported a negative correlation between certain parasite infections and cancer development, we could hypothesize that simple mucin‐type O‐glycosylated antigens obtained from parasites could be good potential targets for cancer immunotherapy. IUBMB Life, 59: 269‐273, 2007

This study evaluates the antitumor immune response induced by human hydatic cyst fluid (HCF) in an animal model of colon carcinoma. We found that anti‐HCF antibodies were able to identify cell surface and intracellular antigens in CT26 colon cancer cells. In prophylactic tumor challenge experiments, HCF vaccination was found to be protective against tumor formation for 40% of the mice (P = 0.01). In the therapeutic setting, HCF vaccination induced tumor regression in 40% of vaccinated mice (P = 0.05). This vaccination generated memory immune responses that protected surviving mice from tumor rechallenge, implicating the development of an adaptive immune response in this process. We performed a proteomic analysis of CT26 antigens recognized by anti‐HCF antibodies to analyze the immune cross‐reactivity between E. granulosus (HCF) and CT26 colon cancer cells. We identified two proteins: mortalin and creatine kinase M‐type. Interestingly, CT26 mortalin displays 60% homology with E. granulosus hsp70. In conclusion, our data demonstrate the capacity of HCF vaccination to induce antitumor immunity which protects from tumor growth in an animal model. This new antitumor strategy could open new horizons in the development of highly immunogenic anticancer vaccines.

The evaluation of disseminated epithelial tumor cells in patients with early stages of breast cancer has generated considerable interest because of its potential association with poor clinical outcome. Considering that O‐glycosylation pathways are frequently altered in breast cancer, we performed this work to evaluate the potential usefulness of UDP‐N‐acetyl‐D‐galactosamine:polypeptide N‐acetylgalactosaminyltransferases (ppGalNAc‐Ts) (a family of glycosyltransferases which catalyze the first key step of mucin‐type O‐glycosylation) to detect disseminated cells in bone marrow samples from patients with operable breast cancer. Using RT‐PCR assays, we studied the gene expression of 9 enzymes (ppGalNAc‐T1–T9). Among the ppGalNAc‐Ts expressed by breast tumors (‐T1, ‐T2, ‐T3, ‐T6 and ‐T7), the best specificity (negative results on all PBMN cell samples from healthy donors) was shown for ppGalNAc‐T6. Thus, we selected this enzyme as a target gene for further evaluation. ppGalNAc‐T6 mRNA was found in 22/25 (88%) breast cancer samples, in all 3 human breast cancer cell lines evaluated (MCF‐7, ZR75‐1 and T47D), in 1/30 (3%) PBMN cells and 0/19 bone marrow samples obtained from patients without cancer. Using this method, 22/61 (36%) patients with breast cancer, who underwent curative surgery, showed positive ppGalNAc‐T6 mRNA in bone marrow aspirates obtained prior to surgery, including 11/34 patients with stage‐I or ‐II, without histopathological lymph node involvement. In a preliminary follow‐up evaluation, 19/61 patients experienced recurrence of the disease. ppGalNAc‐T6 was positive in 11/19 (57.9%) of these patients. Interestingly, in the group of patients without lymph node involvement, disease recurrence was observed in 54.5% of patients who showed ppGalNAc‐T6 mRNA‐positive bone marrow aspirates and only in 4.3% of patients when ppGalNAc‐T6 was negative (p = 0.014). These results indicate that ppGalNAc‐T6 mRNA could be a specific marker applicable to the molecular diagnosis of breast cancer cells dissemination.