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
Affiliations
Dania Zhivaki
Harvard Medical School and Division of Gastroenterology, Boston Children’s Hospital, Boston, MA, USA
Francesco Borriello
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
Ohn A. Chow
Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Benjamin Doran
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
Ira Fleming
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
Derek J. Theisen
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
Paris Pallis
Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
Alex K. Shalek
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
Caroline L. Sokol
Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Ivan Zanoni
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
Jonathan C. Kagan
Harvard Medical School and Division of Gastroenterology, Boston Children’s Hospital, Boston, MA, USA; Corresponding author
Summary: 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.
