Cytoskeletal regulation of dendritic cells: An intricate balance between migration and presentation for tumor therapy

Abstract

Dendritic cells (DCs) are the main players in many approaches for cancer therapy. The idea with DC tumor therapy is to promote activation of tumor infiltrating cytotoxic T cells that kill tumor cells. This requires that DCs take up tumor Ag and present peptides on MHC class I molecules in a process called cross-presentation. For this process to be efficient, DCs have to migrate to the tumor draining lymph node and there activate the machinery for cross-presentation. In this review, we will discuss recent progress in understanding the role of actin regulators for control of DC migration and Ag presentation. The potential to target actin regulators for better DC-based tumor therapy will also be discussed.

Proximity-dependent labeling identifies dendritic cells that drive the tumor-specific CD4+T cell response

“…These included classic DC maturation markers such as Cd80, Cd86, and Cd40 itself 83 , indicative of partial overlap with the canonical "mature DC" phenotype 84 . However, LIPSTIC-labeled DCs also upregulated multiple genes and signatures associated with cell migration, adhesion, and T cell chemotaxis 85 . Thus, the ability of DCs to access specific microanatomical compartments and to recruit T cells to these areas, previously shown to be functionally important for T cell responses [44][45][46]86 , is in fact one of the defining characteristics of the DCs capable of engaging T cells in vivo.…”

Interferon-induced lysosomal membrane permeabilization and death cause cDC1-deserts in tumors

“…A recent study reported a progressive decrease in cDCs1 in lung tumor draining LNs 36 . Both lysosomal stress 66,67 and increased GBP2 68 that we have discovered can change cytoskeleton dynamics and calcium signaling in cDCs1, decreasing their migration 69 . Accordingly, among the top down-regulated genes in our tumor cDC1 dataset there were several related to cytoskeleton and cell adhesion.…”

“…A recent study reported a progressive decrease in cDC1s in tumor draining LNs and indicated a decrease in cDC1 migration rates through unknown mechanisms [26]. We have uncovered three factors that can all change the cytoskeleton dynamics and calcium signaling of cDC1s and thus may impede their migration to LNs[46]: lysosomal stress [47, 48], early apoptosis [49] and increased GBPs [50]. Interestingly, among the top down-regulated genes in tumor cDC1s there were several related to cytoskeleton and cell adhesion, further substantiating such a hypothesis.…”

Increased cross-presentation by dendritic cells and enhanced anti-tumour therapy using the Arp2/3 inhibitor CK666

“…DC uptake, antigen processing and presentation can be modulated in order to improve DC-mediated tumour therapy. Different actin regulators coordinate specific cell responses and it is possible that inhibition of specific actin regulators may be beneficial in supporting different stages of DC maturation and their functionality [25]. CK666 is an Arp2/3 inhibitor that stabilises the inactive state of the complex, blocking the movement of the Arp2 and Arp3 subunits into the activated filament-like (short pitch) conformation [26].…”