Impact of hypoxic tumor microenvironment and tumor cell plasticity on the expression of immune checkpoints

Cancer Lett. 2019 Aug 28:458:13-20. doi: 10.1016/j.canlet.2019.05.021. Epub 2019 May 25.


Compared to traditional therapies, such as surgery, radio-chemotherapy, or targeted approaches, immunotherapies based on immune checkpoint blockers (ICBs) have revolutionized the treatment of cancer. Although ICBs have yielded long-lasting results and have improved patient survival, this success has been seriously challenged by clinical observations showing that only a small fraction of patients benefit from this revolutionary therapy and no benefit has been found in patients with highly aggressive tumors. Efforts are currently ongoing to identify factors that predict the response to ICB. Among the different predictive markers established so far, the expression levels of immune checkpoint genes have proven to be important biomarkers for informing treatment choices. Therefore, understanding the mechanisms involved in the regulation of immune checkpoints is a key element that will facilitate novel combination approaches and optimize patient outcome. In this review, we discuss the impact of hypoxia and tumor cell plasticity on immune checkpoint gene expression and provide insight into the therapeutic value of the EMT signature and the rationale for novel combination approaches to improve ICB therapy and maximize the benefits for patients with cancer.

Keywords: Cancer immunotherapy; Epithelial-to-mesenchymal transition; HIF; Immune checkpoint blockers; Immune suppression; PD-L1 and CD47.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / biosynthesis*
  • B7-H1 Antigen / genetics
  • CD47 Antigen / antagonists & inhibitors
  • CD47 Antigen / biosynthesis*
  • CD47 Antigen / genetics
  • Cell Hypoxia / genetics
  • Cell Hypoxia / immunology
  • Cell Plasticity / genetics
  • Cell Plasticity / immunology
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology


  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD47 Antigen