Indomethacin enhances anti-tumor efficacy of a MUC1 peptide vaccine against breast cancer in MUC1 transgenic mice


Autoři: Jennifer M. Curry aff001;  Dahlia M. Besmer aff001;  Timothy K. Erick aff001;  Nury Steuerwald aff002;  Lopamudra Das Roy aff001;  Priyanka Grover aff001;  Shanti Rao aff001;  Sritama Nath aff001;  Jacob W. Ferrier aff003;  Robert W. Reid aff003;  Pinku Mukherjee aff001
Působiště autorů: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, United States of America aff001;  Molecular Biology and Genomics Laboratory, Carolinas Medical Center, Charlotte, NC, United States of America aff002;  Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, United States of America aff003;  OncoTAb, Inc., Charlotte, NC, United States of America aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224309

Souhrn

In recent years, vaccines against tumor antigens have shown potential for combating invasive cancers, including primary tumors and metastatic lesions. This is particularly pertinent for breast cancer, which is the second-leading cause of cancer-related death in women. MUC1 is a glycoprotein that is normally expressed on glandular epithelium, but is overexpressed and under-glycosylated in most human cancers, including the majority of breast cancers. This under-glycosylation exposes the MUC1 protein core on the tumor-associated form of the protein. We have previously shown that a vaccine consisting of MUC1 core peptides stimulates a tumor-specific immune response. However, this immune response is dampened by the immunosuppressive microenvironment within breast tumors. Thus, in the present study, we investigated the effectiveness of MUC1 vaccination in combination with four different drugs that inhibit different components of the COX pathway: indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), 1-methyl tryptophan (indoleamine 2,3 dioxygenase inhibitor), and AH6809 (prostaglandin E2 receptor antagonist). These treatment regimens were explored for the treatment of orthotopic MUC1-expressing breast tumors in mice transgenic for human MUC1. We found that the combination of vaccine and indomethacin resulted in a significant reduction in tumor burden. Indomethacin did not increase tumor-specific immune responses over vaccine alone, but rather appeared to reduce the proliferation and increase apoptosis of tumor cells, thus rendering them susceptible to immune cell killing.

Klíčová slova:

Apoptosis – Breast cancer – Breast tumors – Cancer treatment – Cancer vaccines – Enzyme-linked immunoassays – Mouse models – Vaccines


Zdroje

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