Guarding epithelial integrity: origins of adaptive immunity and cancer immunosurveillance over time and space

While conventionally viewed as a defense against external pathogens, we posit that the adaptive immune system likely evolved primarily to preserve internal epithelial order. We propose that adaptive immunity, with combinatorial diversity emerging ~0.5 billion years ago during the Cambrian explosion, was based on extant and established complex cellular interactions, derived over the previous 3.5 billion years of life’s history. These coordinate cellular processes originated to police epithelia against aberrant or rogue cells—inherent to complex multicellularity. Primordial surveillance relied on maintaining epithelial integrity and specialized immune sentinels. Early deposition of tissue-resident γδ T and natural killer cells detects abnormalities and emergent stress signals as damage-associated molecular pattern molecules (DAMPs), independently of classical major histocompatibility (MHC) presentation to αβ T cells. Trained immunity in tissue-resident macrophages, stroma, and epithelia reciprocally respond and are tailored by nascent and highly selected tissue-resident memory cells.