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Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade.
- Source :
-
Cell [Cell] 2019 Aug 08; Vol. 178 (4), pp. 933-948.e14. - Publication Year :
- 2019
-
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 (T <subscript>EX</subscript> ). In tumors with favorable antigenicity, these T <subscript>EX</subscript> mediate rejection. In tumors with neoantigen or MHC-I loss, T <subscript>EX</subscript> instead utilize IFNG to drive maturation of innate immune cells, including a PD1 <superscript>+</superscript> TRAIL <superscript>+</superscript> 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.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Adoptive Transfer
Animals
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
CD8-Positive T-Lymphocytes immunology
CTLA-4 Antigen antagonists & inhibitors
Cell Line, Tumor
Cohort Studies
Female
Gene Knockout Techniques
Humans
Interferon-gamma antagonists & inhibitors
Killer Cells, Natural immunology
Lung Neoplasms drug therapy
Melanoma drug therapy
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Programmed Cell Death 1 Receptor antagonists & inhibitors
Progression-Free Survival
RNA-Seq
Transfection
Adaptive Immunity immunology
Immunity, Innate immunology
Interferon-gamma genetics
Interferon-gamma metabolism
Lung Neoplasms immunology
Melanoma immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 178
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 31398344
- Full Text :
- https://doi.org/10.1016/j.cell.2019.07.019