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Immunity. 2016 Apr 19;44(4):924-38. doi: 10.1016/j.immuni.2016.03.012.

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

Author information

1
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis 138648, Singapore.
7
Yale University School of Medicine, New Haven, CT 06510, USA.
8
Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
9
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
10
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: miriam.merad@mssm.edu.

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 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.

PMID:
27096321
PMCID:
PMC4980762
DOI:
10.1016/j.immuni.2016.03.012
[Indexed for MEDLINE]
Free PMC Article

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