Zhivaki et al. observed that DC stimulation with LPS and oxidized phospholipids (a danger-associated molecular pattern) induced a “hyperactive” state characterized by DC inflammasome activity and IL-1β secretion without pyroptotic cell death. Hyperactive DCs increased CCR7 expression and draining lymph node migration, and stimulated robust T cell responses and tumor protection when loaded with tumor antigen. Immunization with LPS, oxidized phospholipids, and tumor-cell lysates extended survival in anti-PD-1-resistant tumor models, dependent on conventional DCs, inflammasomes, IL-1β, and CCR7.
Contributed by Alex Najibi
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-1_, and enable tumor lysates to serve as immunogens. If these activities are verified in humans, hyperactive DCs may impact immunotherapy.
Author Info: (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 H
Author Info: (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 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. (6) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. (7) Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. (8) 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. (9) Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (10) 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. (11) Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.
