Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade.

Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade.

Publication date: Aug 08, 2019

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). In tumors with favorable antigenicity, these T mediate rejection. In tumors with neoantigen or MHC-I loss, T instead utilize IFNG to drive maturation of innate immune cells, including a PD1TRAIL 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.

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., and Minn, A.J. Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade. 23699. 2019 Cell (178):4.

Concepts Keywords
IFNG Tcells T tumors
Immune Checkpoint Blockade Independent tumor
Innate Immune Cells Rejection tumors
Interferon Immunotherapy
Interferon Gamma Medical specialties
Lung Medicine
Melanoma Immune system
MHC I Immunology
Neoantigen Cytokines
PDL1 Antivirals
Perturbation Interferon gamma
TRAIL Immune checkpoint
Tumor PD-L1
Checkpoint inhibitor
Lymphocyte

Semantics

Type Source Name
gene UNIPROT CTLA4
disease DOID lung cancer
disease MESH lung cancer
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
pathway BSID Interferon Signaling
gene UNIPROT TNFSF10
gene UNIPROT PDCD1
gene UNIPROT SPATA2
gene UNIPROT IMPACT
gene UNIPROT CD274
gene UNIPROT IFNG
disease DOID Cancer
disease MESH Cancer

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