Abstract
SUMMARYDendritic 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.
Highlights
Because of their efficient antigen processing and presentation machinery, antigen-presenting cells, such as dendritic cells (DCs), play a central role in the initiation and regulation of specific anti-tumor immunity (Melief, 2008)
To confirm a class effect of microtubule-targeting agents, we tested various microtubule-destabilizing agents (MDAs) and microtubule-stabilizing agents (MSAs) for their capacity to induce DC maturation based on the upregulation of cell surface CD80 and CD86
The targeting of different tubulin-binding sites by MDAs did not correlate with the potency of DC activation (Figure 1A)
Summary
Because of their efficient antigen processing and presentation machinery, antigen-presenting cells, such as dendritic cells (DCs), play a central role in the initiation and regulation of specific anti-tumor immunity (Melief, 2008). DC maturation is necessary for antigen processing and to provide costimulatory signals to T cells (Mildner and Jung, 2014). DC maturation may occur in tumors, it is often insufficient to induce potent immunity and hindered by suppressive mechanisms within tumors (Corrales et al, 2017). In contrast to mature or activated DCs, immature DCs are tolerogenic, are immunosuppressive, and lead to deficient anti-tumor immunity (Gardner and Ruffell, 2016). Bypassing suppressive pathways or directly activating DCs can unleash adaptive immunity through crosspresentation of tumor antigen to generate tumor-specific T cell responses (Wei et al, 2018). The therapeutic targeting of DC maturation or activation processes is a promising strategy to enhance anti-tumor immunity
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