The objective of this work was to demonstrate that the concerted action of tumor-associated antigens [TAAs] and inflammatory cytokines inflict autoimmune damage to the breast creating a chronic inflammatory milieu that promotes breast cancer [BC] progression.
We immunoscreened a T7 cDNA library constructed from mRNA extracted from BC tumors developing in untreated nude mice and performed PCR, sequence determination and homology searches using BLAST AND BLAT to detect signal transduction molecules involved in creating a chronic inflammatory milieu leading to BC progression in the DCIS.com mouse xenograft model of BC. We treated BC developing in the xenograft model with rituximab and dexamethasone. We performed immunohistochemistry [IHC] to monitor the evolution of the human BC developing in the DCIS.com mouse model.
Breast tumor tissue developing in the xenograft model of BC showed deposition of IgG and complement components C1, C2, C3, C4, C5-C9 on breast epithelial and stromal cells and the expression of IL-4, IL-6, IL-17, TNF-alpha and NFkB detected by IHC staining. Immunoscreening a cDNA library identified autoantibodies recognizing multiple human breast epithelial and stromal antigens and the heavy chain and V regions of immunoglobulins IgG1, IgG3, IgM and both light chains, particularly the lambda LC. Rituximab and dexamethasone treatment markedly modified the morphology of developing tumor in BC developing in the xenograft mouse model.
These results suggest that autoantibody- and inflammatory cytokine-mediated autoimmune damage, triggered by TAAs creates a chronic inflammatory milieu with generation of pro-inflammatory and tumor promoting signals supporting BC progression. Thus, in addition to being a protagonist in immune-surveillance, the B cell response in BC may have a tumor-promoting effect. The dramatic results of the treatment of the xenograft model of BC with rituximab and dexamethasone illustrates the potential of adding modalities proven successful in the treatment of the RADs to existing treatments for BC. The demonstration of a major role of autoimmunity in BC progression may have a transformative impact on prevention, diagnosis and treatment of BC.
Felix Fernandez Madrid.
NIH.
All authors have declared no conflicts of interest.