Determining the role of pregnancy-induced IgG antibodies in parity-associated mammary oncoprotection 3099

Abstract Description An early first pregnancy reduces lifelong risk for breast cancer (BC) by ∼30%, partly due to pregnancy-induced changes to mammary immunity. Plasma cells (PCs) and memory B cells (mBCs) accumulate in the mammary gland (MG) during pregnancy and lactation. We are investigating whether pregnancy alters the B cell receptor (BCR) repertoire to enable recognition of mammary self-antigens generated during pregnancy and milk synthesis, some of which are also expressed in BC. We hypothesize that pregnancy-induced IgG antibodies (Abs) augment parity-associated mammary oncoprotection. Using single cell RNA-sequencing, we identified an enrichment of PCs and mBCs in the MGs of parous mice that do not develop mammary tumors after pregnancy, suggesting a role for these cells and Abs in oncoprotection. To explore how pregnancy alters the BCR repertoire, we sequenced BCRs from virgin and parous mouse MGs. We identified five most abundant IgG clonotypes unique to parous MGs and used their BCR sequences to synthesize recombinant pregnancy-induced IgG Abs. Immunofluorescent staining of MGs from various stages of development and tumorigenesis revealed three IgGs that bind to pregnancy-induced antigens that are also present in virgin pre-neoplastic tissue. Our results suggest that pregnancy shapes the BCR repertoire, enabling IgG production against antigens linked to early mammary tumorigenesis. We are now testing whether these recombinant IgGs can block mammary tumorigenesis in mouse models. Funding Sources Breast Cancer Research Foundation; NIH/NIA AG069727-04; NIH/NCI CA248158-04; NIH/NIA CA284630-01; CSHL-Simons Foundation Research Topic Categories Mucosal and Regional Immunology (MUC)