1. Expansion and Activation of CD103+ Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition
- Author
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Brian D. Brown, Romain Remark, Florent Ginhoux, Sacha Gnjatic, Judith Agudo, Marcus Bosenberg, Juliana Idoyaga, Anna Karolina Palucka, Daigo Hashimoto, Stefan Jordan, Maria Casanova-Acebes, Nina Bhardwaj, Marylene Leboeuf, Christina Rivera, Adeeb Rahman, Svetoslav Chakarov, Joshua Brody, Makhzuna Khudoynazarova, Miriam Merad, Navpreet Tung, Hélène Salmon, and Brandon Hogstad
- Subjects
Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Immunology ,Melanoma, Experimental ,Priming (immunology) ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,Cell Line, Tumor ,PD-L1 ,medicine ,Animals ,Immunology and Allergy ,Progenitor cell ,Mice, Knockout ,Antigen Presentation ,biology ,Melanoma ,hemic and immune systems ,Dendritic Cells ,Dendritic cell ,medicine.disease ,3. Good health ,Blockade ,Mice, Inbred C57BL ,Poly I-C ,030104 developmental biology ,Infectious Diseases ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,biology.protein ,Systemic administration ,Cancer research ,Integrin alpha Chains ,CD8 - 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.
- Published
- 2016
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