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

H Salmon, J Idoyaga, A Rahman, M Leboeuf… - Immunity, 2016 - cell.com
H Salmon, J Idoyaga, A Rahman, M Leboeuf, R Remark, S Jordan, M Casanova-Acebes
Immunity, 2016cell.com
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 …
Summary
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.
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