GEF-H1 Signaling upon Microtubule Destabilization Is Required for Dendritic Cell Activation and Specific Anti-tumor Responses
Abhishek S. Kashyap,
Laura Fernandez-Rodriguez,
Yun Zhao,
Gianni Monaco,
Marcel P. Trefny,
Naohiro Yoshida,
Kea Martin,
Ashwani Sharma,
Natacha Olieric,
Pankaj Shah,
Michal Stanczak,
Nicole Kirchhammer,
Sung-Moo Park,
Sebastien Wieckowski,
Heinz Laubli,
Rachid Zagani,
Benjamin Kasenda,
Michel O. Steinmetz,
Hans-Christian Reinecker,
Alfred Zippelius
Affiliations
Abhishek S. Kashyap
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Corresponding author
Laura Fernandez-Rodriguez
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
Yun Zhao
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Gianni Monaco
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
Marcel P. Trefny
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
Naohiro Yoshida
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Kea Martin
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
Ashwani Sharma
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland
Natacha Olieric
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland
Pankaj Shah
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Michal Stanczak
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
Nicole Kirchhammer
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
Sung-Moo Park
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Sebastien Wieckowski
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
Heinz Laubli
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland; Medical Oncology, University Hospital Basel, 4031 Basel, Switzerland
Rachid Zagani
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Benjamin Kasenda
Medical Oncology, University Hospital Basel, 4031 Basel, Switzerland
Michel O. Steinmetz
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland; University of Basel, Biozentrum, 4056 Basel, Switzerland
Hans-Christian Reinecker
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Corresponding author
Alfred Zippelius
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland; Medical Oncology, University Hospital Basel, 4031 Basel, Switzerland; Corresponding author
Summary: Dendritic cell (DC) activation is a critical step for anti-tumor T cell responses. Certain chemotherapeutics can influence DC function. Here we demonstrate that chemotherapy capable of microtubule destabilization has direct effects on DC function; namely, it induces potent DC maturation and elicits anti-tumor immunity. Guanine nucleotide exchange factor-H1 (GEF-H1) is specifically released upon microtubule destabilization and is required for DC activation. In response to chemotherapy, GEF-H1 drives a distinct cell signaling program in DCs dominated by the c-Jun N-terminal kinase (JNK) pathway and AP-1/ATF transcriptional response for control of innate and adaptive immune responses. Microtubule destabilization, and subsequent GEF-H1 signaling, enhances cross-presentation of tumor antigens to CD8 T cells. In absence of GEF-H1, anti-tumor immunity is hampered. In cancer patients, high expression of the GEF-H1 immune gene signature is associated with prolonged survival. Our study identifies an alternate intracellular axis in DCs induced upon microtubule destabilization in which GEF-H1 promotes protective anti-tumor immunity. : Certain chemotherapeutics elicit potent anti-tumor immunity. Kashyap et al. demonstrate that microtubule-destabilizing chemotherapeutics induce maturation of dendritic cells through activation of microtubule-associated protein GEF-H1. This leads to effective priming of CD8 T cells against tumor antigens. GEF-H1 is critical for anti-tumor immunity of microtubule-targeting chemotherapy. Keywords: GEF-H1, lfc, dendritic cells, microtubule-targeting agents, cross presentation, JNK pathway, ansamitocin-P3, plinabulin, immunotherapy, chemotherapy
