Expansion and Activation of CD103+ Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition

Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103+ dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8+ T cells. CD103+ DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103+ DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103+ DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade. [Display omitted] •CD103+ DCs are uniquely able to transport intact antigens to the TdLN and prime CD8+ T cells•CD103+ DCs are required to induce anti-PD-L1-Ab-mediated anti-tumor immunity•Combined FLT3L and poly I:C therapy induces expansion and activation of CD103+ DC progenitors in tumors•Combined FLT3L and poly I:C therapy enhances tumor responses to BRAF and checkpoint blockade Large numbers of melanoma patients develop resistance to targeted therapy or fail to respond to checkpoint inhibition. Merad and colleagues show that FLT3L and poly I:C combined treatment, which expands and activates CD103+ DC progenitors at the tumor site, enhances tumor responses to BRAF and PD-L1 blockade.