Expansion and activation of CD103 ⁺ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition

Abstract

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 PDL1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the cytokine 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 Flt3L-poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.

Graphical Abstract