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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

Insertion of α-gal glycolipids into the lipid bilayer of tumor cell membranes. α-gal glycolipid molecules dissolve in water or saline as micelles (ball like structures with the cross-section described in this figure) in which the hydrophobic (lipophilic) ceramide chains are clustered in the core. When these micelles are adjacent to cells, individual α-gal glycolipid molecules “jump” into the outer leaflet of the cell lipid bilayer, because the energetic state of the ceramide tail surrounded by phospholipids is much more stable than in micelles surrounded by water. α-gal glycolipid insertion into the tumor cell membrane results in expression of α-gal epitopes on the cell. Binding of the natural anti-Gal antibody to these epitopes leads to destruction of tumor cells and their uptake by APC.
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cancers-02-00773-f002: Insertion of α-gal glycolipids into the lipid bilayer of tumor cell membranes. α-gal glycolipid molecules dissolve in water or saline as micelles (ball like structures with the cross-section described in this figure) in which the hydrophobic (lipophilic) ceramide chains are clustered in the core. When these micelles are adjacent to cells, individual α-gal glycolipid molecules “jump” into the outer leaflet of the cell lipid bilayer, because the energetic state of the ceramide tail surrounded by phospholipids is much more stable than in micelles surrounded by water. α-gal glycolipid insertion into the tumor cell membrane results in expression of α-gal epitopes on the cell. Binding of the natural anti-Gal antibody to these epitopes leads to destruction of tumor cells and their uptake by APC.

Mentions: The micelles of α-gal glycolipids are submicroscopic spherical structures in which the inner part is comprised of the hydrophobic fatty acid tails of the ceramide. The outer part the micelle is formed by the hydrophilic carbohydrate chains (Figure 2). When such micelles are brought near tumor cells, the α-gal glycolipid molecules “jump” into the cell membrane and the ceramide portion inserts into it. Therefore, the carbohydrate chains carrying α-gal epitopes protrudes out of the cell membrane. This insertion occurs spontaneously because the hydrophobic lipid tails of the α-gal glycolipids are energetically much more stable within cell membranes where they are surrounded by phospholipids, than within micelles that are surrounded by water (Figure 2). Therefore, injection of micelles made of α-gal glycolipids into tumor lesions results in insertion of the α-gal glycolipids into the membranes of cells within the injected lesion and expression of α-gal epitopes on tumor cells, somewhat comparable to those naturally occurring on xenograft cells [52].


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)

Insertion of α-gal glycolipids into the lipid bilayer of tumor cell membranes. α-gal glycolipid molecules dissolve in water or saline as micelles (ball like structures with the cross-section described in this figure) in which the hydrophobic (lipophilic) ceramide chains are clustered in the core. When these micelles are adjacent to cells, individual α-gal glycolipid molecules “jump” into the outer leaflet of the cell lipid bilayer, because the energetic state of the ceramide tail surrounded by phospholipids is much more stable than in micelles surrounded by water. α-gal glycolipid insertion into the tumor cell membrane results in expression of α-gal epitopes on the cell. Binding of the natural anti-Gal antibody to these epitopes leads to destruction of tumor cells and their uptake by APC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475649&req=5

cancers-02-00773-f002: Insertion of α-gal glycolipids into the lipid bilayer of tumor cell membranes. α-gal glycolipid molecules dissolve in water or saline as micelles (ball like structures with the cross-section described in this figure) in which the hydrophobic (lipophilic) ceramide chains are clustered in the core. When these micelles are adjacent to cells, individual α-gal glycolipid molecules “jump” into the outer leaflet of the cell lipid bilayer, because the energetic state of the ceramide tail surrounded by phospholipids is much more stable than in micelles surrounded by water. α-gal glycolipid insertion into the tumor cell membrane results in expression of α-gal epitopes on the cell. Binding of the natural anti-Gal antibody to these epitopes leads to destruction of tumor cells and their uptake by APC.
Mentions: The micelles of α-gal glycolipids are submicroscopic spherical structures in which the inner part is comprised of the hydrophobic fatty acid tails of the ceramide. The outer part the micelle is formed by the hydrophilic carbohydrate chains (Figure 2). When such micelles are brought near tumor cells, the α-gal glycolipid molecules “jump” into the cell membrane and the ceramide portion inserts into it. Therefore, the carbohydrate chains carrying α-gal epitopes protrudes out of the cell membrane. This insertion occurs spontaneously because the hydrophobic lipid tails of the α-gal glycolipids are energetically much more stable within cell membranes where they are surrounded by phospholipids, than within micelles that are surrounded by water (Figure 2). Therefore, injection of micelles made of α-gal glycolipids into tumor lesions results in insertion of the α-gal glycolipids into the membranes of cells within the injected lesion and expression of α-gal epitopes on tumor cells, somewhat comparable to those naturally occurring on xenograft cells [52].

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