Targeting Dendritic Cells

The Roles of DCs

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) and have a central role in maintaining immune homeostasis. There are multiple subclassifications of DCs, however, these can broadly be grouped into conventional DC type 1 (cDC1), conventional DC type 2 (cDC2), and plasmacytoid DCs (pDCs). In general, mature DCs have been considered immune-stimulatory, whereas immature ones have been considered suppressive and tolerogenic. Mature DCs can migrate to tumor-draining lymph nodes to prime T cell responses, recruit T cells into the TME and produce immunostimulatory cytokines that condition the TME.

Based on their attributes, such as activation status, maturity, and polarization in TME, DCs' functional plasticity is considered complicated. They mainly have a dual function in the tumor microenvironment (TME). On one hand, DCs acquire, process, and present tumor-associated antigens (TAAs) on MHC molecules and provide costimulation and soluble factors to shape T cell responses. On the other hand, under the pressure of antitumor immunity, cancer cell variants can arise that exploit DCs to promote immune tolerance. Presentation of TAAs in the absence of costimulatory signals leads to T cell anergy.

Modulation of DCs Function by Tumors

Numerous studies have demonstrated the presence of tumor-infiltrating DCs (TIDCs) in a variety of tumor types. However, TIDCs often show quantitative and functional deficiencies in the TME, such as the reduction in mature functional DCs and the local aggregation of immature or regulatory DCs. The TME also contains a network of immunosuppressive factors that can inhibit DCs infiltration and subdue their antitumor activity. Tumors secrete a variety of factors that can: (1) inhibit differentiation of DC from precursors, (2) induce differentiation of DC precursors into immunosuppressive myeloid-derived suppressor cells (MDSC) or tumor-associated macrophages (TAM), (3) suppress maturation, activation, and stimulatory APC function of already differentiated DC, and (4) induce the development of immunosuppressive regulatory DC. Targeting these immunosuppressive pathways therapeutically may improve the recruitment, infiltration, and effector activity of T cells in the TME.

DCs-based Immunotherapies

Tumors that progress do so via their ability to escape the anti-tumor immune response through several mechanisms, including developing ways to impair functional differentiation and activation of DCs. Thus, regulating DCs is important in improving current cancer therapies. The strategies for targeting DCs are focusing on their functional improvement, expansion, and tumor-derived antigen specificities.

• Activation of DCs

One method to increase the functionality of DCs is to administer cytokines, such as FLT3LG and granulocyte-macrophage colony-stimulating factor (GM-CSF), which promote the differentiation and activation of DCs. In addition to cytokines, TLR signaling and cGAS-STING pathway are critical for DC activation in the antitumor immune response.

• Administration of antigens to boost antitumor immunity

In vivo administration of TAAs that can be presented (or cross-presented) by endogenous DCs has historically been an attractive cancer immunotherapy approach.

• DC vaccines

DC vaccination is active immunotherapy that aims at inducing an antitumoral immune response. Combining DC vaccines with therapies targeting the three immunosuppressive cell populations of the TME-regulatory T cells (Treg), TAM, or MDSC-might improve antitumor efficacy, modulate the inflammatory conditions in the TME and block the mechanisms of immunosuppression.

Creative Biolabs is committed to sharing our technologies, platforms, and experience to facilitate your projects. Equipped with a team of professional scientists, we are capable of providing specialized support in reshaping TME. DCs-based services include DCs vaccines and DCs gene delivery system. Please feel free to contact us for more information.