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.