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Cancer immunotherapy targeting the high molecular weight melanoma-associated antigen protein results in a broad antitumor response and reduction of pericytes in the tumor vasculature.
- Source :
-
Cancer research [Cancer Res] 2008 Oct 01; Vol. 68 (19), pp. 8066-75. - Publication Year :
- 2008
-
Abstract
- The high molecular weight melanoma-associated antigen (HMW-MAA), also known as melanoma chondroitin sulfate proteoglycan, has been used as a target for the immunotherapy of melanoma. This antigen is expressed on the cell surface and has a restricted distribution in normal tissues. Besides its expression in a broad range of transformed cells, this antigen is also found in pericytes, which are important for tumor angiogenesis. We generated a recombinant Listeria monocytogenes (Lm-LLO-HMW-MAA-C) that expresses and secretes a fragment of HMW-MAA (residues 2,160-2,258) fused to the first 441 residues of the listeriolysin O (LLO) protein. Immunization with Lm-LLO-HMW-MAA-C was able to impede the tumor growth of early established B16F10-HMW-MAA tumors in mice and both CD4(+) and CD8(+) T cells were required for therapeutic efficacy. Immune responses to a known HLA-A2 epitope present in the HMW-MAA(2160-2258) fragment was detected in the HLA-A2/K(b) transgenic mice immunized with Lm-LLO-HMW-MAA-C. Surprisingly, this vaccine also significantly impaired the in vivo growth of other tumorigenic cell lines, such as melanoma, renal carcinoma, and breast tumors, which were not engineered to express HMW-MAA. One hypothesis is that the vaccine could be targeting pericytes, which are important for tumor angiogenesis. In a breast tumor model, immunization with Lm-LLO-HMW-MAA-C caused CD8(+) T-cell infiltration in the tumor stroma and a significant decrease in the number of pericytes in the tumor blood vessels. In conclusion, a Lm-based vaccine against HMW-MAA can trigger cell-mediated immune responses to this antigen that can target not only tumor cells but also pericytes in the tumor vasculature.
- Subjects :
- Animals
Antigens, Neoplasm metabolism
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes pathology
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes pathology
Cancer Vaccines metabolism
Cancer Vaccines therapeutic use
Female
Immunity, Cellular immunology
Listeria monocytogenes metabolism
Melanoma, Experimental blood supply
Melanoma, Experimental pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Pericytes immunology
Recombinant Proteins metabolism
Recombinant Proteins therapeutic use
Treatment Outcome
Tumor Cells, Cultured
Antigens, Neoplasm immunology
Immunotherapy methods
Melanoma, Experimental immunology
Melanoma, Experimental therapy
Neovascularization, Pathologic pathology
Pericytes pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 68
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 18829565
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-08-0287