LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy

Nat Commun. 2019 Jun 11;10(1):2416. doi: 10.1038/s41467-019-10369-9.


Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Chemokine CCL2 / metabolism
  • Chemokine CXCL9 / metabolism*
  • Epigenesis, Genetic
  • Humans
  • Immunologic Memory
  • Leukemia Inhibitory Factor / antagonists & inhibitors
  • Leukemia Inhibitory Factor / immunology*
  • Leukemia Inhibitory Factor / metabolism
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Mice, SCID
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Tumor Microenvironment / immunology


  • Antibodies, Neutralizing
  • CCL2 protein, human
  • CXCL9 protein, human
  • Chemokine CCL2
  • Chemokine CXCL9
  • Leukemia Inhibitory Factor
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor