Abstract P4-04-03: Monocytic immature myeloid cells permit tumor immune evasion during postpartum involution

Abstract

Abstract Young women with breast cancer diagnosed in the postpartum period, defined as up to 5 years from last child delivery, have a poorer prognosis compared to women who have never been pregnant, and represent ∼30% of all young women's breast cancer cases. Our lab has proposed that the poor prognosis associated with postpartum breast cancer is due to gland remodeling following pregnancy, known as postpartum involution. Using rodent models and human breast tissue, it has been demonstrated recently that postpartum gland involution utilizes wound healing programs to remodel the gland to a non-secretory state. For example, macrophages with tumor promotional characteristics have been identified as essential mediators of epithelial cell death during postpartum involution. We hypothesize that the immune cells within the normal involuting gland set up an immunosuppressive environment to protect the host from negative sequel resulting from potential self-antigen exposure during epithelial cell death. A consequence would be the establishment of an immune microenvironment that favors the growth and metastasis of breast cancer cells. To characterize the role of immune cells during normal postpartum involution as well as in the promotion of mammary cancer, we developed an immunocompetent mouse model of postpartum breast cancer using the Balb/c mouse. By flow cytometry, we found that dendritic cells, GR1+ monocytic immature myeloid cells (IMCs), and T cells increase exponentially in the mammary gland during involution. Functional assays using myeloid cells from the mammary gland indicate the IMCs isolated from involuting glands are capable of suppressing T cell activation ex vivo, consistent with immune suppression in vivo. To begin to investigate whether IMCs are able to promote tumor progression in the postpartum breast cancer setting, D2A1 mammary carcinoma were injected into mammary fat pads of Balb/c mice. D2A1 cells injected into hosts with actively involuting mammary glands had a significant growth advantage over tumor cells injected into nulliparous host glands, demonstrating that mammary gland involution promotes the growth of mammary carcinoma cells in this immune competent model. T cells identified by flow cytometry are significantly lower in number systemically and within the tumors of the involution-group compared to the nulliparous-group, indicating systemic immunosuppression specific to the involution-group. To demonstrate immunosuppressive function, IMCs were isolated from tumors and incubated with T cells ex vivo. IMCs from involution tumors were significantly more suppressive then IMCs from nulliparous mice. These data indicate IMCs play an immunomodulatory role in the mammary gland during involution, which allows tumor cells to undergo immune evasion in the postpartum period. We are currently investigating how GR1+ IMCs suppress T cell activation and hope to determine if reprograming these cells could prevent the promotion of breast cancer during involution. (DOD-BC10904 and BC100910) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-04-03.