Unraveling the mechanisms underlying dendritic cell clustering within the tumor microenvironment

The tumor microenvironment (TME) hosts various immune cells including dendritic cells (DCs). DCs
are pivotal in initiating anti-tumor responses by capturing tumor-associated antigens (TAs) and
transporting them to the tumor-draining lymph node (tdLN), where they prime anti-tumor T cells.
Recent studies have highlighted that DC-T cell interactions are not restricted to the tdLN. Instead,
DCs recruit, restimulate, and induce the expansion of anti-tumor CD8+ T cells within the TME by
presenting TAs and secreting cytokines that regulate CD8+ T cell survival and effector functions. To
this end, a number of DCs reside in the TME and form clusters that provide a niche for these DC-T
cell interactions. However, the mechanisms by which intratumoral DC clusters are formed remain
unknown. Here, I aim to identify the molecules and signaling axes involved in the formation of these
intratumoral DC clusters. First, I will define the spatiotemporal dynamics of DC cluster formation
using photoconvertible mice. Second, I will assess the role of distinct chemokine receptors (CCRs) in
the formation of DC clusters by employing Ccr7-/- mice and CRISPR-Cas9 knockout screens. Finally, I
will evaluate the effect of the DC-modulating therapies anti-CD40 agonist and fascin inhibitor on the
formation of the DC clusters. The findings of this proposal will provide novel insight into fundamental
DC biology and their role within the TME, which can lead to the design of innovative
immunotherapies