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

PLoS One. 2019 Nov 6;14(11):e0224309. doi: 10.1371/journal.pone.0224309. eCollection 2019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / immunology
  • Breast Neoplasms / therapy*
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / immunology
  • Combined Modality Therapy / methods
  • Cyclooxygenase Inhibitors / administration & dosage*
  • Female
  • Humans
  • Immunogenicity, Vaccine / drug effects
  • Immunogenicity, Vaccine / immunology
  • Indomethacin / administration & dosage*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / therapy*
  • Mice
  • Mice, Transgenic
  • Mucin-1 / genetics
  • Mucin-1 / immunology*
  • Tumor Burden / drug effects
  • Tumor Burden / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Vaccines, Subunit / administration & dosage
  • Vaccines, Subunit / immunology

Substances

  • Cancer Vaccines
  • Cyclooxygenase Inhibitors
  • MUC1 protein, human
  • Mucin-1
  • Vaccines, Subunit
  • muc1 protein, mouse
  • Indomethacin

Grant support

This work was supported by Department of Defense Award (CDMRP BCRP 10578683), and by Susan G. Komen Breast Cancer Foundation Research Grant (KG101475). This work was also funded by Irwin Belk Endowment from UNCC. Pinku Mukherjee is the founder and Chief Scientific Officer (CSO) of OncoTAb, Inc., a startup company that owns patents and rights to the TAB004 antibody and markets the TAB004-based ELISA as a Laboratory Developed Test under the commercial name AgkuraTM Personal Score. OncoTAb, Inc. provided support in the form of salary for Pinku Mukherjee, but did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.