Pairwise Interaction Govern The Effects Of Complex Immune Adjuvant Combinations

Abstract The immune system decides upon actions in response to complex combinations of microbial inputs. Dozens of innate immune sensing pathways can collectively respond to combinations of microbial and immunomodulatory agents such as adjuvants. We currently lack a clear understanding for the combinatorial logic that governs how the interplay between higher-order combinations of microbial or adjuvant signals shape immune responses. Here, using in vitro coculture experiments and statistical analyses, we uncover an intrinsic property of pathogen-sensing pathways whereby the effects of higher-order combinations of stimuli on immune responses can be explained by single and pairwise effects. Surprisingly, this property of combinatorial innate sensing is mechanistically rooted in the molecular organization underlying pathogen-sensing pathways. Indeed, we find that the outputs of mouse and human innate immune dendritic cells upon triplet stimulations are dictated by single and pairwise effects at the levels of transcription, chromatin and protein secretion. Furthermore, we exploit this simplifying property of combinatorial pathogen sensing to develop and characterize cell-based immunotherapies with potent anti-tumor properties in mouse models using combinations of adjuvants. We conclude that the processing of complex mixtures of microbial or adjuvant inputs by immune cells is governed by pairwise effects, which suggests a path towards the rationale selection of adjuvant combinations to alter immunity.