The process is divided into four main steps. Step 1, Enhance cDC1 availability, includes expansion via FLT3L delivery and cDC1 cell-based vaccines or CAR cDC1s. Step 2, Promote intratumoral recruitment, involves delivering chemokines like XCL1 to the tumor microenvironment. Step 3, cDC1 activation and licensing, includes PRR agonism or radiotherapy and the use of CD40 agonist antibodies or bispecifics. Step 4, Relieve immune suppression, involves blocking suppressive signaling pathways with anti-IL-4 and anti-IL-6, and depleting Treg and MDSC cells using antibody-mediated methods. The flowchart shows the interaction and sequence of these steps to achieve optimal cDC1-mediated anti-tumor immunity.
Therapeutic strategies to promote cDC1 antitumor function. Strategies aiming to harness cDC1s for antitumor functionality include (i) cDC1 expansion via the local or systemic delivery of growth/differentiation factors including FLT3L, and/or delivery of cDC1-based vaccine platforms and CAR cDC1s; (ii) cDC1 maturation via systemic targeted delivery of PRR agonists or localized radiotherapy; (iii) cDC1 activity enhancement via the agonism of cell surface molecules including CD40 and delivery of key cytokines including IL-12; (iv) cDC1 lymphatic or intratumoral homing via the delivery of key chemokines including XCL1; (v) depletion of immunosuppressive cell types that limit cDC1 functionality in the TME including Tregs and MDSCs; and (vi) the blockade of immunosuppressive pathways that limit cDC1 activity or differentiation including IL-4 and IL-6.