Epithelial cell glycoprotein MUC1 is overexpressed and hypoglycosylated on all human adenocarcinomas and is recognized by the immune system as a tumor antigen. In basic and preclinical studies supported by the long-standing grant that this application aims to renew, we have deciphered numerous interactions of MUC1 and the adaptive immune system and this knowledge has been translated to MUC1 based vaccines for pancreatic, breast, colon and prostate cancer. We also made an unexpected observation that MUC1 interacts directly with the cells of the innate immune system and thus might play an important role in inflammation and cancer. Our hypothesis is that overexpression and aberrant glycosylation of MUC1 promotes first chronic inflammation and later progression to cancer and thus MUC1 should be targeted not only for tumor therapy, as studied so far, but also for therapy of chronic inflammation before tumors develop. We propose two specific aims:
Specific Aim 1. To define MUC1 related cellular and molecular events that regulate (induce, promote) chronic inflammation and cancer. We will use the new mouse model developed in the previous grant period as well as the information we obtained regarding the novel interactions of the MUC1 glycoprotein with the innate and the adaptive immune system.
Specific Aim 2. To test the ability of MUC1-specific or MUC1-related immunotherapy to prevent chronic inflammation and cancer. We will use vaccines based on immunogenic MUC1 glycopeptides defined in the last grant period as well as MUC1 specific TCR transgenic mice developed in the same period. We have preliminary evidence that inducing MUC1 specific adaptive immunity can prevent not only cancer but also chronic inflammation. Nobody has yet considered MUC1 as a target for therapy, and specifically immunotherapy, of chronic inflammatory diseases that carry increased risk of cancer.

Public Health Relevance

This is a long-standing project directed towards immunotherapy of cancer and cancer vaccines based on the tumor antigen MUC1. In this renewal application, work will be done to show that this form of immunotherapy and the same vaccines may be useful not only for cancer but also for treatment and prevention of chronic inflammations that increase risk for cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Iheagwara, Uzoma K; Beatty, Pamela L; Van, Phu T et al. (2014) Influenza virus infection elicits protective antibodies and T cells specific for host cell antigens also expressed as tumor-associated antigens: a new view of cancer immunosurveillance. Cancer Immunol Res 2:263-73
Marvel, Douglas M; Finn, Olivera J (2014) Global Inhibition of DC Priming Capacity in the Spleen of Self-Antigen Vaccinated Mice Requires IL-10. Front Immunol 5:59
Finn, Olivera J (2014) Vaccines for cancer prevention: a practical and feasible approach to the cancer epidemic. Cancer Immunol Res 2:708-13
Cascio, Sandra; Farkas, Adam M; Hughey, Rebecca P et al. (2013) Altered glycosylation of MUC1 influences its association with CIN85: the role of this novel complex in cancer cell invasion and migration. Oncotarget 4:1686-97
Cascio, Sandra; Zhang, Lixin; Finn, Olivera J (2011) MUC1 protein expression in tumor cells regulates transcription of proinflammatory cytokines by forming a complex with nuclear factor-ýýB p65 and binding to cytokine promoters: importance of extracellular domain. J Biol Chem 286:42248-56
Ryan, Sean O; Turner, Michael S; Gariepy, Jean et al. (2010) Tumor antigen epitopes interpreted by the immune system as self or abnormal-self differentially affect cancer vaccine responses. Cancer Res 70:5788-96
Kadayakkara, Deepak K; Beatty, Pamela L; Turner, Michael S et al. (2010) Inflammation driven by overexpression of the hypoglycosylated abnormal mucin 1 (MUC1) links inflammatory bowel disease and pancreatitis. Pancreas 39:510-5
Beatty, Pamela L; Narayanan, Sowmya; Gariepy, Jean et al. (2010) Vaccine against MUC1 antigen expressed in inflammatory bowel disease and cancer lessens colonic inflammation and prevents progression to colitis-associated colon cancer. Cancer Prev Res (Phila) 3:438-46
Ryan, Sean O; Vlad, Anda M; Islam, Kazi et al. (2009) Tumor-associated MUC1 glycopeptide epitopes are not subject to self-tolerance and improve responses to MUC1 peptide epitopes in MUC1 transgenic mice. Biol Chem 390:611-8
Chen, Xiaochuan; Gao, Wentao; Gambotto, Andrea et al. (2009) Lentiviral vectors encoding human MUC1-specific, MHC-unrestricted single-chain TCR and a fusion suicide gene: potential for universal and safe cancer immunotherapy. Cancer Immunol Immunother 58:977-87

Showing the most recent 10 out of 46 publications