De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors

Nat Immunol. 2017 Nov;18(11):1207-1217. doi: 10.1038/ni.3836. Epub 2017 Sep 11.


The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / pharmacology
  • Drug Resistance, Neoplasm / immunology
  • Drug Therapy, Combination
  • Immunotherapy / methods*
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Mice, Inbred C3H
  • Mice, Transgenic
  • Neoplasms / blood supply
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Neovascularization, Pathologic / immunology
  • Neovascularization, Pathologic / therapy*
  • Peptides / administration & dosage
  • Peptides / genetics
  • Peptides / pharmacology
  • Survival Analysis
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Treatment Outcome
  • Tumor Microenvironment / immunology*
  • Tumor Necrosis Factor Ligand Superfamily Member 14 / chemistry
  • Tumor Necrosis Factor Ligand Superfamily Member 14 / genetics


  • Cancer Vaccines
  • Peptides
  • Tnfsf14 protein, mouse
  • Tumor Necrosis Factor Ligand Superfamily Member 14