Breast Cancer Associated Metastasis is Significantly Increased in a Model of Autoimmune Arthritis

Chronic inflammation is known to play a role in cancer initiation, promotion,and metastasis. However, the mechanism by which inflammation promotes metastasis is still unclear. We evaluated if chronic inflammation induced by autoimmune arthritis may contribute to increased breast cancer-associated metastasis. We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic mice compared to control mice. The metastatic breast tumors in turn augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as IL-17, IL-6, VEGF, and TNF-α were the underlying factors contributing to the increased metastasis. The data clearly has important clinical implications for patients diagnosed with metastatic breast cancer

Aberrant Glycosylation of Anchor-Optimized MUC1 Peptides Can Enhance Antigen Binding Affinity and Reverse Tolerance to Cytotoxic T Lymphocytes

Cancer vaccines have often failed to live up to their promise, although recent results with checkpoint inhibitors are reviving hopes that they will soon fulfill their promise. Although mutation-specific vaccines are under development, there is still high interest in an off-the-shelf vaccine to a ubiquitous antigen, such as MUC1, which is aberrantly expressed on most solid and many hematological tumors, including more than 90% of breast carcinomas. Clinical trials for MUC1 have shown variable success, likely because of immunological tolerance to a self-antigen and to poor immunogenicity of tandem repeat peptides. We hypothesized that MUC1 peptides could be optimized, relying on heteroclitic optimizations of potential anchor amino acids with and without tumor-specific glycosylation of the peptides. We have identified novel MUC1 class I peptides that bind to HLA-A*0201 molecules with significantly higher affinity and function than the native MUC1 peptides. These peptides elicited CTLs from normal donors, as well as breast cancer patients, which were highly effective in killing MUC1-expressing MCF-7 breast cancer cells. Each peptide elicited lytic responses in greater than 6/8 of normal individuals and 3/3 breast cancer patients. The CTLs generated against the glycosylated-anchor modified peptides cross reacted with the native MUC1 peptide, STAPPVHNV, suggesting these analog peptides may offer substantial improvement in the design of epitope-based vaccines