Inflammasomes within Hyperactive Murine Dendritic Cells Stimulate Long-Lived T Cell-Mediated Anti-tumor Immunity

Dania Zhivaki; Francesco Borriello; Ohn A Chow; Benjamin Doran; Ira Fleming; Derek J Theisen; Paris Pallis; Alex K Shalek; Caroline L Sokol; Ivan Zanoni; Jonathan C Kagan

doi:10.1016/j.celrep.2020.108381

Inflammasomes within Hyperactive Murine Dendritic Cells Stimulate Long-Lived T Cell-Mediated Anti-tumor Immunity

Cell Rep. 2020 Nov 17;33(7):108381. doi: 10.1016/j.celrep.2020.108381.

Authors

Affiliations

¹ Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
² Harvard Medical School and Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
³ Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁴ Department of Chemistry, Institute for Medical Engineering and Sciences (IMES), Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02142, USA; Ragon Institute of MGH, Harvard, and MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School and Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
⁸ Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.

Abstract

Central to anti-tumor immunity are dendritic cells (DCs), which stimulate long-lived protective T cell responses. Recent studies have demonstrated that DCs can achieve a state of hyperactivation, which is associated with inflammasome activities within living cells. Herein, we report that hyperactive DCs have an enhanced ability to migrate to draining lymph nodes and stimulate potent cytotoxic T lymphocyte (CTL) responses. This enhanced migratory activity is dependent on the chemokine receptor CCR7 and is associated with a unique transcriptional program that is not observed in conventionally activated or pyroptotic DCs. We show that hyperactivating stimuli are uniquely capable of inducing durable CTL-mediated anti-tumor immunity against tumors that are sensitive or resistant to PD-1 inhibition. These protective responses are intrinsic to the cDC1 subset of DCs, depend on the inflammasome-dependent cytokine IL-1β, and enable tumor lysates to serve as immunogens. If these activities are verified in humans, hyperactive DCs may impact immunotherapy.

Keywords: CD8+ T cells; IL-1β; anti-tumor immunity; dendritic cells; hyperactivation; inflammasomes; pyroptosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity / immunology*
Animals
Cell Line
Cell Line, Tumor
Cell Movement / physiology
Dendritic Cells / immunology*
Female
Humans
Immunotherapy
Inflammasomes / immunology*
Lymph Nodes / metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Receptors, CCR7 / immunology
Receptors, CCR7 / metabolism
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / metabolism

Substances

Ccr7 protein, mouse
Inflammasomes
Receptors, CCR7

Abstract

Publication types

MeSH terms

Substances

Grants and funding