GEF-H1 Signaling upon Microtubule Destabilization Is Required for Dendritic Cell Activation and Specific Anti-tumor Responses

Cell Rep. 2019 Sep 24;28(13):3367-3380.e8. doi: 10.1016/j.celrep.2019.08.057.

Abstract

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.

Keywords: GEF-H1; JNK pathway; ansamitocin-P3; chemotherapy; cross presentation; dendritic cells; immunotherapy; lfc; microtubule-targeting agents; plinabulin.

Publication types

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

MeSH terms

  • Cell Differentiation
  • Dendritic Cells / metabolism*
  • Humans
  • Microtubules / metabolism*
  • Neoplasms / metabolism*
  • Rho Guanine Nucleotide Exchange Factors / metabolism*
  • Signal Transduction / immunology*

Substances

  • ARHGEF2 protein, human
  • Rho Guanine Nucleotide Exchange Factors