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In Situ Conversion of Melanoma Lesions into Autologous Vaccine by Intratumoral Injections of α-gal Glycolipids.

Galili U, Albertini MR, Sondel PM, Wigglesworth K, Sullivan M, Whalen GF - Cancers (Basel) (2010)

Bottom Line: Most require effective uptake by antigen presenting cells (APC).Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC.The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.

ABSTRACT
Autologous melanoma associated antigens (MAA) on murine melanoma cells can elicit a protective anti-tumor immune response following a variety of vaccine strategies. Most require effective uptake by antigen presenting cells (APC). APC transport and process internalized MAA for activation of anti-tumor T cells. One potential problem with clinical melanoma vaccines against autologous tumors may be that often tumor cells do not express surface markers that label them for uptake by APC. Effective uptake of melanoma cells by APC might be achieved by exploiting the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. This approach has been developed in a syngeneic mouse model using mice capable of producing anti-Gal. Anti-Gal binds specifically to α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). Injection of glycolipids carrying α-gal epitopes (α-gal glycolipids) into melanoma lesions results in glycolipid insertion into melanoma cell membranes, expression of α-gal epitopes on the tumor cells and binding of anti-Gal to these epitopes. Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC. The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases. A clinical trial is now open testing effects of intratumoral α-gal glycolipid injections in melanoma patients.

No MeSH data available.


Related in: MedlinePlus

Ceramide pentahexoside (CPH) (left) and ceramide decahexoside (CDecaH) (right) as representative α-gal glycolipids. CPH is the most abundant glycolipid in rabbit RBC and is presented as a schematic α-gal glycolipid with five carbohydrates. CDecaH is a glycolipid with 10 carbohydrate branched chain. α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) are marked by the broken line rectangles. The terminal α-galactosyl (Gal) is linked α1,3 to the penultimate Gal of the carbohydrate chain by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT). The carbohydrate chain is linked to the lipid portion (ceramide) embedded in the cell membrane via the two fatty acid tails. Anti-Gal binding to α-gal epitopes is presented as schematic IgG molecules. α-gal glycolipids in rabbit RBC (with the exception of ceramide heptahexoside) increase in size in increments of five carbohydrates, each forming an additional branch that is capped by α-gal epitopes.
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cancers-02-00773-f001: Ceramide pentahexoside (CPH) (left) and ceramide decahexoside (CDecaH) (right) as representative α-gal glycolipids. CPH is the most abundant glycolipid in rabbit RBC and is presented as a schematic α-gal glycolipid with five carbohydrates. CDecaH is a glycolipid with 10 carbohydrate branched chain. α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) are marked by the broken line rectangles. The terminal α-galactosyl (Gal) is linked α1,3 to the penultimate Gal of the carbohydrate chain by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT). The carbohydrate chain is linked to the lipid portion (ceramide) embedded in the cell membrane via the two fatty acid tails. Anti-Gal binding to α-gal epitopes is presented as schematic IgG molecules. α-gal glycolipids in rabbit RBC (with the exception of ceramide heptahexoside) increase in size in increments of five carbohydrates, each forming an additional branch that is capped by α-gal epitopes.

Mentions: Anti-Gal is the most abundant natural antibody in human serum, constituting ~1% of serum IgG [28]. It is produced as a result of continuous antigenic stimulation by bacteria of the gastrointestinal flora [29]. Anti-Gal interacts specifically with a carbohydrate antigen called the α-gal epitope that has the structure Galα1-3Galβ1-4GlcNAc-R [30,31]. The α-gal epitope is present on cell surface glycolipids and glycoproteins of nonprimate marsupial and placental mammals, in prosimians and New World monkeys (monkeys of South America), [32,33,34]. With the exception of spermatozoa, all cells tested in these species were found to express many α-gal epitopes [32,33,34,35]. The α-gal epitope on mammalian glycolipids is illustrated in Figure 1. α-gal epitopes are synthesized on carbohydrate chains of glycolipids and glycoproteins in the Golgi apparatus of mammalian cells by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT) [33,35]. All mammals producing α-gal epitopes lack the natural anti-Gal antibody, whereas, humans, apes, and Old World monkeys (monkeys of Asia and Africa) lack α-gal epitopes due to inactivation of the α1,3GT gene in ancestral primates, but they all produce the natural anti-Gal antibody [32,33,34,35,36].


In Situ Conversion of Melanoma Lesions into Autologous Vaccine by Intratumoral Injections of α-gal Glycolipids.

Galili U, Albertini MR, Sondel PM, Wigglesworth K, Sullivan M, Whalen GF - Cancers (Basel) (2010)

Ceramide pentahexoside (CPH) (left) and ceramide decahexoside (CDecaH) (right) as representative α-gal glycolipids. CPH is the most abundant glycolipid in rabbit RBC and is presented as a schematic α-gal glycolipid with five carbohydrates. CDecaH is a glycolipid with 10 carbohydrate branched chain. α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) are marked by the broken line rectangles. The terminal α-galactosyl (Gal) is linked α1,3 to the penultimate Gal of the carbohydrate chain by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT). The carbohydrate chain is linked to the lipid portion (ceramide) embedded in the cell membrane via the two fatty acid tails. Anti-Gal binding to α-gal epitopes is presented as schematic IgG molecules. α-gal glycolipids in rabbit RBC (with the exception of ceramide heptahexoside) increase in size in increments of five carbohydrates, each forming an additional branch that is capped by α-gal epitopes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475649&req=5

cancers-02-00773-f001: Ceramide pentahexoside (CPH) (left) and ceramide decahexoside (CDecaH) (right) as representative α-gal glycolipids. CPH is the most abundant glycolipid in rabbit RBC and is presented as a schematic α-gal glycolipid with five carbohydrates. CDecaH is a glycolipid with 10 carbohydrate branched chain. α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) are marked by the broken line rectangles. The terminal α-galactosyl (Gal) is linked α1,3 to the penultimate Gal of the carbohydrate chain by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT). The carbohydrate chain is linked to the lipid portion (ceramide) embedded in the cell membrane via the two fatty acid tails. Anti-Gal binding to α-gal epitopes is presented as schematic IgG molecules. α-gal glycolipids in rabbit RBC (with the exception of ceramide heptahexoside) increase in size in increments of five carbohydrates, each forming an additional branch that is capped by α-gal epitopes.
Mentions: Anti-Gal is the most abundant natural antibody in human serum, constituting ~1% of serum IgG [28]. It is produced as a result of continuous antigenic stimulation by bacteria of the gastrointestinal flora [29]. Anti-Gal interacts specifically with a carbohydrate antigen called the α-gal epitope that has the structure Galα1-3Galβ1-4GlcNAc-R [30,31]. The α-gal epitope is present on cell surface glycolipids and glycoproteins of nonprimate marsupial and placental mammals, in prosimians and New World monkeys (monkeys of South America), [32,33,34]. With the exception of spermatozoa, all cells tested in these species were found to express many α-gal epitopes [32,33,34,35]. The α-gal epitope on mammalian glycolipids is illustrated in Figure 1. α-gal epitopes are synthesized on carbohydrate chains of glycolipids and glycoproteins in the Golgi apparatus of mammalian cells by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT) [33,35]. All mammals producing α-gal epitopes lack the natural anti-Gal antibody, whereas, humans, apes, and Old World monkeys (monkeys of Asia and Africa) lack α-gal epitopes due to inactivation of the α1,3GT gene in ancestral primates, but they all produce the natural anti-Gal antibody [32,33,34,35,36].

Bottom Line: Most require effective uptake by antigen presenting cells (APC).Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC.The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.

ABSTRACT
Autologous melanoma associated antigens (MAA) on murine melanoma cells can elicit a protective anti-tumor immune response following a variety of vaccine strategies. Most require effective uptake by antigen presenting cells (APC). APC transport and process internalized MAA for activation of anti-tumor T cells. One potential problem with clinical melanoma vaccines against autologous tumors may be that often tumor cells do not express surface markers that label them for uptake by APC. Effective uptake of melanoma cells by APC might be achieved by exploiting the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. This approach has been developed in a syngeneic mouse model using mice capable of producing anti-Gal. Anti-Gal binds specifically to α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). Injection of glycolipids carrying α-gal epitopes (α-gal glycolipids) into melanoma lesions results in glycolipid insertion into melanoma cell membranes, expression of α-gal epitopes on the tumor cells and binding of anti-Gal to these epitopes. Interaction between the Fc portions of bound anti-Gal and Fcγ receptors on APC induces effective uptake of tumor cells by APC. The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases. A clinical trial is now open testing effects of intratumoral α-gal glycolipid injections in melanoma patients.

No MeSH data available.


Related in: MedlinePlus