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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / immunology
  • Antigens, CD / metabolism*
  • B7-H1 Antigen / antagonists & inhibitors*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Integrin alpha Chains / metabolism*
  • Melanoma, Experimental / immunology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly I-C / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / pharmacology*

Substances

  • Antigens, CD
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Integrin alpha Chains
  • alpha E integrins
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf
  • Poly I-C