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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

Anti-Gal mediated targeting of tumor cells to APC in lesions injected with α-gal glycolipids. Anti-Gal IgG binds in situ to α-gal epitopes on α-gal glycolipids inserted into tumor cell membranes. Subsequent interaction between the Fc portion of the bound anti-Gal and FcγR on the APC (schematic illustration of a dendritic cell) induces uptake of intact or lysed tumor cells by APC and thus, effective internalization of the tumor antigens (MAA in melanoma lesions). Internalized tumor antigens are processed and various immunogenic tumor antigen peptides (●) are presented by the APC in association with class I and class II MHC molecules. These immunogenic peptides can activate tumor specific T cells and elicit a protective anti-tumor immune response.
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cancers-02-00773-f005: Anti-Gal mediated targeting of tumor cells to APC in lesions injected with α-gal glycolipids. Anti-Gal IgG binds in situ to α-gal epitopes on α-gal glycolipids inserted into tumor cell membranes. Subsequent interaction between the Fc portion of the bound anti-Gal and FcγR on the APC (schematic illustration of a dendritic cell) induces uptake of intact or lysed tumor cells by APC and thus, effective internalization of the tumor antigens (MAA in melanoma lesions). Internalized tumor antigens are processed and various immunogenic tumor antigen peptides (●) are presented by the APC in association with class I and class II MHC molecules. These immunogenic peptides can activate tumor specific T cells and elicit a protective anti-tumor immune response.

Mentions: The destruction of melanoma lesions achieved by various ablation methods is likely to be more effective than the tumor destruction achieved by intratumoral injection of α-gal glycolipids (Figure 4). However, whereas the immune system may remain “oblivious” to MAA of ablated lesions, the intratumoral injection of α-gal glycolipids converts the treated lesion into an endogenous autologous tumor vaccine which elicits an immune response against autologous MAA. Anti-Gal IgG molecules bound to α-gal epitopes on glycolipids inserted into tumor cell membranes opsonize the melanoma cells and target them for effective uptake by APC, such as dendritic cells and macrophages (Figure 5). This uptake is the result of the interaction between the Fc portion of anti-Gal bound to the tumor cells and FcγR on APC [48,62]. As argued above, this anti-Gal mediated targeting of cells in injected lesions increases the immunogenicity of tumor antigens expressed in the internalized cells or cell membranes.


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)

Anti-Gal mediated targeting of tumor cells to APC in lesions injected with α-gal glycolipids. Anti-Gal IgG binds in situ to α-gal epitopes on α-gal glycolipids inserted into tumor cell membranes. Subsequent interaction between the Fc portion of the bound anti-Gal and FcγR on the APC (schematic illustration of a dendritic cell) induces uptake of intact or lysed tumor cells by APC and thus, effective internalization of the tumor antigens (MAA in melanoma lesions). Internalized tumor antigens are processed and various immunogenic tumor antigen peptides (●) are presented by the APC in association with class I and class II MHC molecules. These immunogenic peptides can activate tumor specific T cells and elicit a protective anti-tumor immune response.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

cancers-02-00773-f005: Anti-Gal mediated targeting of tumor cells to APC in lesions injected with α-gal glycolipids. Anti-Gal IgG binds in situ to α-gal epitopes on α-gal glycolipids inserted into tumor cell membranes. Subsequent interaction between the Fc portion of the bound anti-Gal and FcγR on the APC (schematic illustration of a dendritic cell) induces uptake of intact or lysed tumor cells by APC and thus, effective internalization of the tumor antigens (MAA in melanoma lesions). Internalized tumor antigens are processed and various immunogenic tumor antigen peptides (●) are presented by the APC in association with class I and class II MHC molecules. These immunogenic peptides can activate tumor specific T cells and elicit a protective anti-tumor immune response.
Mentions: The destruction of melanoma lesions achieved by various ablation methods is likely to be more effective than the tumor destruction achieved by intratumoral injection of α-gal glycolipids (Figure 4). However, whereas the immune system may remain “oblivious” to MAA of ablated lesions, the intratumoral injection of α-gal glycolipids converts the treated lesion into an endogenous autologous tumor vaccine which elicits an immune response against autologous MAA. Anti-Gal IgG molecules bound to α-gal epitopes on glycolipids inserted into tumor cell membranes opsonize the melanoma cells and target them for effective uptake by APC, such as dendritic cells and macrophages (Figure 5). This uptake is the result of the interaction between the Fc portion of anti-Gal bound to the tumor cells and FcγR on APC [48,62]. As argued above, this anti-Gal mediated targeting of cells in injected lesions increases the immunogenicity of tumor antigens expressed in the internalized cells or cell membranes.

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