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.
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.
Hélène
H
Salmon
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Juliana
J
Idoyaga
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Adeeb
A
Rahman
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.
Marylène
M
Leboeuf
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.
Romain
R
Remark
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.
Stefan
S
Jordan
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.
Maria
M
Casanova-Acebes
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.
Makhzuna
M
Khudoynazarova
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.
Judith
J
Agudo
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.
Navpreet
N
Tung
Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis 138648, Singapore.
Svetoslav
S
Chakarov
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.
Christina
C
Rivera
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.
Brandon
B
Hogstad
Yale University School of Medicine, New Haven, CT 06510, USA.
Marcus
M
Bosenberg
Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Daigo
D
Hashimoto
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.
Sacha
S
Gnjatic
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.
Nina
N
Bhardwaj
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
Anna Karolina
AK
Palucka
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.
Brian D
BD
Brown
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.
Joshua
J
Brody
Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis 138648, Singapore.
Florent
F
Ginhoux
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.
Miriam
M
Merad
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D039001:Integrin alpha Chains / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051941:fms-Like Tyrosine Kinase 3 / Q000494:pharmacology*
D015703:Antigens, CD; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D039001:Integrin alpha Chains; C091367:alpha E integrins; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D011070:Poly I-C