In-silico insights on the prognostic potential of immune cell infiltration patterns in the breast lobular epithelium

Abstract

Scattered inflammatory cells are commonly observed in mammary gland tissue, most likely in response to normal cell turnover by proliferation and apoptosis, or as part of immunosurveillance. In contrast, lymphocytic lobulitis (LLO) is a recurrent inflammation pattern, characterized by lymphoid cells infiltrating lobular structures, that has been associated with increased familial breast cancer risk and immune responses to clinically manifest cancer. The mechanisms and pathogenic implications related to the inflammatory microenvironment in breast tissue are still poorly understood. Currently, the definition of inflammation is mainly descriptive, not allowing a clear distinction of LLO from physiological immunological responses and its role in oncogenesis remains unclear. To gain insights into the prognostic potential of inflammation, we developed an agent-based model of immune and epithelial cell interactions in breast lobular epithelium. Physiological parameters were calibrated from breast tissue samples of women who underwent reduction mammoplasty due to orthopedic or cosmetic reasons. The model allowed to investigate the impact of menstrual cycle length and hormone status on inflammatory responses to cell turnover in the breast tissue. Our findings suggested that the immunological context, defined by the immune cell density, functional orientation and spatial distribution, contains prognostic information previously not captured by conventional diagnostic approaches.

Image analysis of immune cell patterns in the human mammary gland during the menstrual cycle refines lymphocytic lobulitis

“…We observed a heterogeneous occurrence of immune cells within tissue samples of an individual and between pa-tients. This was consistent with our previous results in a subset of the present series, recently described in [1]. In general, there was a high number of CD8 + Tlymphocytes, about seven per 100 epithelial cells on average.…”

“…As another example, we envision that the combination of focal CD4 + T-cells in predominantly stromal localization, along with CD8 + T-cell clusters in the neighborhood of destroyed or disintegrating lobular epithe-lium could be a distinguishing feature. This is based on the observation that this pattern was rarely present in the 53 normal breast samples of the current study, but repeatedly seen in an independent series of archival prophylactic mastectomy samples [1] in patients with BRCA1/2 germline mutations (see two representative examples in Fig. 7 of the Online Resource 1).…”

“…Breast tissue was obtained from 53 premenopausal healthy women who underwent reduction mammoplasty and provided a detailed reproductive clinical history [12,13,1]. 20 women were taking oral contraceptives at time of surgery (Table 1).…”

Therapeutic Potential of Bacteria against Solid Tumors

“…Then, we use a mathematical model that combines vascularized tumor growth and effector cell recruitment dynamics to gain insights into the possible reasons of success or failure of bacterial therapies. Mathematical models have been rather successful in investigating the biology of cancer (23)(24)(25)(26) and are becoming an increasingly important resource to address immunologic questions (27)(28)(29), as well as useful for optimizing and predicting antitumor therapy outcomes (9,27,(30)(31)(32)(33)(34)(35)(36). Model analysis not only provides a qualitative and quantitative explanation of experimental results, but also allows for novel therapeutic strategies.…”

Multiscale Agent-Based and Hybrid Modeling of the Tumor Immune Microenvironment

“…Alfonso et al developed an agent-based model of immune cell-epithelial cell interactions in breast lobular epithelium[93]. The model investigated the effect of menstrual cycle length and hormone status on inflammatory response to cell turnover in breast tissue.…”