The Local Immune Landscape Determines Tumor PD-L1 Heterogeneity and Sensitivity to Therapy

J Clin Invest. 2019 May 21;129(8):3347-3360. doi: 10.1172/JCI127726.

Abstract

PD-L1 is a promising therapeutic target in aggressive cancers. However, immune landscapes and cancer hallmarks of human PD-L1+ tumors, as well as their roles in determining therapeutic efficacies are unknown. Here we identified, in detailed studies of gene data regarding 9769 patients of 32 types of human cancers, that PD-L1 could not exclusively represent IFN-γ signature and potentially signified pro-inflammatory myeloid responses in a tumor. PD-L1 heterogeneity endowed by local immune landscapes controlled cancer hallmarks and clinical outcomes of patients. Mechanically, NF-κB signal elicited by macrophage inflammatory responses generated PD-L1+ cancer cells exhibiting capabilities to aggressively survive, support angiogenesis, and metastasize, whereas STAT1 signal triggered by activated T cells induced PD-L1+ cancer cells susceptive to apoptosis. Importantly, PD-L1+ cancer cells generated by macrophages established great resistance to conventional chemotherapy, cytotoxicity of tumor-specific effector T cells, and therapy of immune checkpoint blockade. Therapeutic strategy combining immune checkpoint blockade with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited caner regression. Our results provide insight into the functional features of PD-L1+ tumors and suggest that strategies to influence functional activities of inflammatory cells may benefit immune checkpoint blockade therapy.

Keywords: Cancer immunotherapy; Immunology; Inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • B7-H1 Antigen / immunology*
  • Female
  • Hep G2 Cells
  • Humans
  • Immunotherapy*
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Neoplasm Proteins / immunology*
  • Neoplasms* / immunology
  • Neoplasms* / pathology
  • Neoplasms* / therapy
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / pathology
  • Xenograft Model Antitumor Assays

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Neoplasm Proteins