Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade Journal Article

   

Authors:	Benci, J. L.; Johnson, L. R.; Choa, R.; Xu, Y.; Qiu, J.; Zhou, Z.; Xu, B.; Ye, D.; Nathanson, K. L.; June, C. H.; Wherry, E. J.; Zhang, N. R.; Ishwaran, H.; Hellmann, M. D.; Wolchok, J. D.; Kambayashi, T.; Minn, A. J.
Article Title:	Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade
Abstract:	Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection. In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of innate immune cells, including a PD1+TRAIL+ ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden. The opposing effects of interferon-gamma in terms of regulating immune function but also driving T cell exhaustion through PDL1 is explained by its differential effects in tumor and immune cell populations. © 2019 Elsevier Inc.
Keywords:	interferon; nk cells; immune checkpoint blockade; innate lymphoid cells; ctla4; t cell exhaustion; pdl1; immunotherapy resistance; isgs
Journal Title:	Cell
Volume:	178
Issue:	4
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2019-08-08
Start Page:	933
End Page:	948.e14
Language:	English
DOI:	10.1016/j.cell.2019.07.019
PUBMED:	31398344
PROVIDER:	scopus
PMCID:	PMC6830508
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85069924248&doi=10.1016%2fj.cell.2019.07.019&partnerID=40&md5=6d74c89fa8ed2a852b372b111a30a1f2
Notes:	Article -- Source: Scopus

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