Reciprocal immune-epithelial interaction during breast cancer induction

Abstract

The notion of immune editing and its defined phases (elimination, equilibrium, and escape), once a transformed cell emerges, is now well established. What occurs prior to, and may in fact impact, transformation-inflammation, initiation, and inception of malignancy-has been a murkier proposition. These "three I's" form the basis of a concept we put forth called reciprocal learning, which we define as a constant crosstalk in non-diseased tissue between the local epithelial cells and immune cells that occurs across the lifespan. Epithelial cells and resident macrophages provide the basis for genetic and epigenetic alterations as a site for learning by adaptive immune cells. Conversely, epithelial cells learn which changes are recognized by both innate and adaptive immune cells by modulating expression of MHC molecules and the antigen processing and presentation machinery. This "reciprocal learning" that occurs between the local epithelium and immune system provides memory for the immune system to then respond to dysregulated epithelial growth across the lifespan. We illustrate this with important recent findings of immune cells within the normal breast. An immune response is most certainly present (surveilling) the breast epithelium from the onset of mammary gland development, during active menstrual cycling, during lactation, and in the postmenopausal period with involution. We speculate that this reciprocal learning may be one of the main reasons why seven out of eight women do not get breast cancer in their lifetime.

Keywords: Breast Cancer; Immune modulatory; Tumor microenvironment - TME.

Figure 1. Inflammation, initiation, and inception as precursors to the cancer-immunoediting hypothesis. Early immune-epithelial interaction between nascent dysregulated epithelial cells and both the innate and adaptive immune arms shapes downstream elimination, equilibrium, and escape in the cancer immunoediting scheme. Inflammation refers to the local inflammation in the breast that occurs with proliferation and involution during the menstrual cycle as well as during aging; initiation refers to the necessary acquired somatic changes that promote proliferation; lastly, during inception, further genomic changes in the epithelia allow transformation with reciprocal learning promoting immune elimination. There is likely overlap between the three I’s and the three E’s.

Figure 2. Physiologic reciprocal learning in the normal breast epithelium and immune cells. In the basal state, reciprocal learning occurs at the cellular level between the adaptive immune cells (mainly CD8+ and CD4+ T cells) in the normal breast. Several conditions may enhance reciprocal learning: (1) cells with high germline epitope burden may promote an immune response and possible tumor clearance; (2) aneuploid cells in the normal breast may allow immune cells to “learn” about emergent genomic instability and expression of novel epitopes; (3) menstrual cycling, where cell proliferation associated with local inflammation may promote immune surveillance. A few conditions may also diminish reciprocal learning: (1) increased host age; (2) unresolved or excessive inflammation such as that occurring during infection; (3) exogenous or environmental conditions that promote microbiome disturbance. New approaches are warranted to better understand reciprocal communication between breast epithelial cells and immune cells. Because there are a finite number of driver genes in breast cancer that we know of, we predict that specific epitope targets encoded by the genome are present during budding morphogenesis or menstrual cycle-related proliferation and may serve to provide “information” to the immune system, limiting subsequent abnormal epithelial growth later in life.