IL-1α Mediates Innate and Acquired Resistance to Immunotherapy in Melanoma.
Animals
Cell Line, Tumor
Cytokines
/ immunology
Drug Resistance, Neoplasm
/ immunology
Humans
Immune Checkpoint Inhibitors
/ immunology
Immunotherapy
/ methods
Interleukin-1alpha
/ immunology
Kaplan-Meier Estimate
Melanoma, Experimental
/ immunology
Mice, Inbred C57BL
Myeloid-Derived Suppressor Cells
/ immunology
Neutrophils
/ immunology
Signal Transduction
/ drug effects
Tumor Microenvironment
/ drug effects
Journal
Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
Titre abrégé: J Immunol
Pays: United States
ID NLM: 2985117R
Informations de publication
Date de publication:
15 04 2021
15 04 2021
Historique:
received:
08
05
2020
accepted:
03
02
2021
pubmed:
17
3
2021
medline:
31
8
2021
entrez:
16
3
2021
Statut:
ppublish
Résumé
Inflammation has long been associated with cancer initiation and progression; however, how inflammation causes immune suppression in the tumor microenvironment and resistance to immunotherapy is not well understood. In this study, we show that both innate proinflammatory cytokine IL-1α and immunotherapy-induced IL-1α make melanoma resistant to immunotherapy. In a mouse melanoma model, we found that tumor size was inversely correlated with response to immunotherapy. Large tumors had higher levels of IL-1α, Th2 cytokines, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and regulatory T cells but lower levels of IL-12, Th1 cytokines, and activated T cells. We found that therapy with adenovirus-encoded CD40L (rAd.CD40L) increased tumor levels of IL-1α and PMN-MDSCs. Blocking the IL-1 signaling pathway significantly decreased rAd.CD40L-induced PMN-MDSCs and their associated PD-L1 expression in the tumor microenvironment and enhanced tumor-specific immunity. Similarly, blocking the IL-1 signaling pathway improved the antimelanoma activity of anti-PD-L1 Ab therapy. Our study suggests that blocking the IL-1α signaling pathway may increase the efficacy of immunotherapies against melanoma.
Identifiants
pubmed: 33722878
pii: jimmunol.2000523
doi: 10.4049/jimmunol.2000523
pmc: PMC8023145
doi:
Substances chimiques
Cytokines
0
Immune Checkpoint Inhibitors
0
Interleukin-1alpha
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1966-1975Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA093459
Pays : United States
Organisme : Department of Defense
ID : CA160521
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021 by The American Association of Immunologists, Inc.
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