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.
Highlights
Autologous melanoma associated antigens (MAA) on murine melanoma cells can elicit a protective anti-tumor immune response following a variety of vaccine strategies
One potential approach to destroy residual micrometastases may be the use of immunotherapy, i.e., stimulation of the immune system to detect and destroy tumor cells expressing melanoma associated antigens (MAA)
Careful evaluation of in vitro responses of melanoma patients, those receiving experimental forms of immunotherapy, have provided insights regarding human MAA and components of the immune response involved in their recognition
Summary
Appearance of metastases that are refractory to therapy is usually lethal. The assumption that the immune system in humans is capable of detecting and destroying tumor cells carrying autologous tumor antigens is based primarily on retrospective studies demonstrating a distinct correlation between the extent of T cell infiltration into tumors inspected post resection, and prognosis in the individual patient [5,6,7,8] These reported correlations imply that the immune system in some patients is capable of developing a specific protective response against antigens that are unique to the tumor cells. Expressed on their tumor cells (i.e., a unique autologous tumor antigen) indicated that after initial destruction of many tumor cells, the tumor evades the elicited immune response by selective development of tumor cells that lack the isotype [9,10] This implies that effective immunotherapy may require the induction of an immune response against multiple antigens specific to the tumors cells in the treated patient in order to prevent escape from anti-tumor immunity via the loss of a sole tumor antigen. -gal glycolipids, induce their destruction and further induce an active anti-tumor immune response
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