Abstract 2365: Determining the role of pregnancy-induced IgG antibodies in parity-associated mammary oncoprotection

Abstract An early age of first pregnancy reduces the lifelong risk of developing breast cancer (BC) by ∼30%. The dos Santos Lab has shown that pregnancy-induced alterations to the mammary immune microenvironment, including adaptive immune cells, are crucial for the oncoprotective effect of pregnancy. While plasma cells and memory B cells in the pregnant/lactating mammary gland (MG) are largely appreciated for their role in secreting antibodies into breastmilk, B cells may also encounter and secrete antibodies against self-antigens that arise during pregnancy-associated MG development and milk synthesis. Several antigens expressed in the pregnant/lactating MG are also expressed in BC. As a result, we hypothesize that pregnancy induces IgG production against antigens associated with pregnancy and mammary tumorigenesis, contributing to parity-associated mammary oncoprotection. To obtain an unbiased profile of pregnancy-induced alterations to the mammary immune microenvironment, we performed single cell RNA-sequencing on virgin and parous non-tumor-bearing mammary tissue from a mouse model of pregnancy-induced mammary oncoprotection (Brca1 loss of function). Our analysis reveals an enrichment of plasma cells and memory B cells in the parous MG, raising the question of whether these cells and their antibody production may play a role in the inhibition of mammary tumorigenesis in parous mice in this model. To understand whether pregnancy induces alterations to the antigens recognized by B cells, we performed BCR-sequencing of MGs from virgin and parous wildtype mice. Using clonotype abundance analysis, we identified five IgG clonotypes that were most abundant and unique to the parous MGs. We used the BCR sequences of these clonotypes to synthesize five recombinant pregnancy-induced IgG antibodies. Through immunofluorescent staining analysis of mammary tissue from various stages of development and tumorigenesis, we have identified three clones that bind to pregnancy-induced mammary epithelial antigens that are also present in virgin pre-neoplastic mammary tissue. These results suggest that pregnancy may influence the BCR repertoire and enable IgG production against antigens expressed by pre-neoplastic cells in the MG. We are testing whether these recombinant pregnancy-induced IgG antibodies can be administered in vivo and inhibit mammary tumorigenesis in mouse models of BC. Citation Format: Dhivyaa Anandan, Marygrace Trousdell, Amritha Varshini Hanasoge Somasundara, Johannes T.-H. Yeh, Camila O. dos Santos. Determining the role of pregnancy-induced IgG antibodies in parity-associated mammary oncoprotection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2365.