Carbohydrate Research 389 (2014) 115–122
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Glycans in immune recognition and response Ron Amon, Eliran Moshe Reuven, Shani Leviatan Ben-Arye, Vered Padler-Karavani ⇑ Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
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Article history: Received 27 November 2013 Received in revised form 29 January 2014 Accepted 2 February 2014 Available online 12 February 2014 Keywords: Sialic acid Neu5Gc Antibodies Cancer Immunotherapy Biomarker
a b s t r a c t Glycans at the forefront of cells facilitate immune recognition processes. Cancer cells commonly present altered cell surface glycosylation, especially manifested in the expression of sialic acid at the termini of glycolipids and glycoproteins. Although tumor-associated carbohydrate antigens (TACAs) result in expression of altered-self, most such carbohydrates do not elicit strong humoral responses. Various strategies had been devised to elicit increased immunogenicity of such TACA aiming for potent immunotherapeutic antibodies or cancer vaccines. However some carbohydrates are immunogenic in humans and hold potential for novel glycotherapies. N-Glycolylneuraminic acid (Neu5Gc) is a foreign immunogenic sugar in humans originating from the diet (e.g., red meat) and subsequently expressed on the cell surface, especially accumulating on carcinoma. Consequently, the human immune system detects this non-self carbohydrate generating a broad anti-Neu5Gc antibody response. The co-existence of Neu5Gc/antiNeu5Gc within humans spurs chronic inflammation mediated disease, including cancer. Concurrently, anti-Neu5Gc antibodies hold potential for novel targeted therapy. aGal is another foreign immunogenic carbohydrate antigen in humans and all humans have circulating anti-Gal antibodies. This review aims to describe the immunogenicity of Neu5Gc and its implications for human diseases, highlighting differences and similarities with aGal and its potential for novel targeted theranostics. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction The immune system discriminates self from non-self and eliminates particles carrying such non-self determinants. Pathogens can evade immune recognition either by masking non-self antigens and/or by disguising with host self-antigens through molecular mimicry. However, some pathological conditions present alteredself determinants that cause breaching of tolerance and lead to rejection through an autoimmune response.103 Cell surface glycosylation is universal to all living cells and strategically positioned to mediate such immune recognition processes.107,155 Carbohydrate chains (glycans) that decorate glycoproteins and glycolipids (glycoconjugates) on the cell surface hold tremendous structural diversity.120,155 In vertebrates, glycans usually terminate with sialic acids (Sia) that function as markers of normal self and can be recognized by a variety of receptors (e.g., Siglecs) mediating inter- and intra-cellular communication.129,152 Cancer cells commonly present altered cell surface glycosylation as a result of abnormal expression of glycosyltransferases giving rise to changes in the typical glycan structures and/or to their expression levels.11,153 Such changes especially affect sialylation
⇑ Corresponding author. Tel.: +972 3 640 6792; fax: +972 3 642 2046. E-mail address: vkaravani@post.tau.ac.il (V. Padler-Karavani). http://dx.doi.org/10.1016/j.carres.2014.02.004 0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.
patterns33,85,86,122 that correlate with an advanced cancer stage, progression and/or metastasis.11,57,78,122,139 Although such tumorassociated carbohydrate antigens (TACAs) result in expression of altered-self, most of these carbohydrates are largely poorly immunogenic and do not result in potent antibody responses,60 with a few exceptions.90,96 Nevertheless, carbohydrates have been shown to be involved in other aspects of tumor immunology and can contribute to cellular immune responses within immunoediting and immunosurveillance processes.14,24,116,137 For example, it was shown that tumor cells with a lower degree of sialylation can interact better with immunosurveilling cells.24 TACA holds tremendous potential for targeted cancer therapy and in recent years efforts have been put into eliciting increased immunogenicity of such TACA aiming to generate potent antibodies for immunotherapy or a vaccine that can provoke a specific immune response against cancer.52,71,164,166 Several approaches to improving TACA immunogenicity have been investigated: covalently coupling of carbohydrates to immunologically active protein carriers such as bovine serum albumin (BSA), keyhole limpet hemocyanin (KLH), tetanus toxoid (TT), or Bacille Calmette–Guérin (BCG);52,166 treating with a mixture of several mono-epitopic vaccines;95,133 or fully synthetic homogeneous vaccines designed to contain an adjuvant or other immunological epitopes to further enhance the immunogenicity of resulting vaccines.12,13,73 Many of these new strategies were very successful at improving