@article{617ed8b9e3ba4d058a29f3014cae9178,
title = "Pairwise Stimulations of Pathogen-Sensing Pathways Predict Immune Responses to Multi-adjuvant Combinations",
abstract = "The immune system makes decisions in response to combinations of multiple microbial inputs. We do not understand the combinatorial logic governing how higher-order combinations of microbial signals shape immune responses. Here, using coculture experiments and statistical analyses, we discover a general property for the combinatorial sensing of microbial signals, whereby the effects of triplet combinations of microbial signals on immune responses can be predicted by combining the effects of single and pairs. Mechanistically, we find that singles and pairs dictate the information signaled by triplets in mouse and human DCs at the levels of transcription, chromatin, and protein secretion. We exploit this simplifying property to develop cell-based immunotherapies prepared with adjuvant combinations that trigger protective responses in mouse models of cancer. We conclude that the processing of multiple input signals by innate immune cells is governed by pairwise effects, which will inform the rationale combination of adjuvants to manipulate immunity.",
keywords = "adjuvants, cancer immunotherapy, cell therapy, innate immunity, pattern-recognition receptors",
author = "Surya Pandey and Adam Gruenbaum and Tamara Kanashova and Philipp Mertins and Philippe Cluzel and Nicolas Chevrier",
note = "Funding Information: We thank Hugo Carillon, Vikram Juneja, Motohiko Kadoki, and Peter Sage for help with pilot experiments; Stefano Allesina, Albert Bendelac, Aaron Esser-Kahn, Andrew Ferguson, Thomas Gajewski, Jeffrey Hubbell, Andrew Murray, Arvind Murugan, Rama Ranganathan, Peter Savage, Melody Swartz, and Savas Tay for valuable discussions; and Sigrid Knemeyer for help with artwork. P.C. was supported by an NSF grant Physics of Living Systems (# 129334 ). N.C. was supported by an NIH Director{\textquoteright}s New Innovator award ( DP2 AI145100 ), an institutional research grant (# IRG-16-222-56 ) from the American Cancer Society , the University of Chicago Medicine Comprehensive Cancer Center Support grant (# P30 CA14599 ), the Elliot and Ruth Sigal MRA Young Investigator Award, and funds from the Bauer Fellows Program and the Pritzker School of Molecular Engineering . Funding Information: We thank Hugo Carillon, Vikram Juneja, Motohiko Kadoki, and Peter Sage for help with pilot experiments; Stefano Allesina, Albert Bendelac, Aaron Esser-Kahn, Andrew Ferguson, Thomas Gajewski, Jeffrey Hubbell, Andrew Murray, Arvind Murugan, Rama Ranganathan, Peter Savage, Melody Swartz, and Savas Tay for valuable discussions; and Sigrid Knemeyer for help with artwork. P.C. was supported by an NSF grant Physics of Living Systems (#129334). N.C. was supported by an NIH Director's New Innovator award (DP2 AI145100), an institutional research grant (#IRG-16-222-56) from the American Cancer Society, the University of Chicago Medicine Comprehensive Cancer Center Support grant (#P30 CA14599), the Elliot and Ruth Sigal MRA Young Investigator Award, and funds from the Bauer Fellows Program and the Pritzker School of Molecular Engineering. Conceptualization, P.C. and N.C.; Methodology, S.P. and N.C.; Investigation, S.P. and N.C.; Mass spectrometry analysis, T.K. and P.M.; Pairwise analytical framework, P.C.; Formal Analysis, A.G. P.C. and N.C.; Writing – Original Draft, S.P. and N.C.; Writing – Review & Editing, S.P. A.G. T.K. P.M. P.C. and N.C.; Funding Acquisition, P.C. and N.C.; Supervision, N.C. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = nov,
day = "18",
doi = "10.1016/j.cels.2020.10.001",
language = "English (US)",
volume = "11",
pages = "495--508.e10",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "5",
}
