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

Abstract

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