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Mass Cytometry Analysis of Systemic and Local Immune Responses in Hepatocellular Carcinoma
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The Liver-Immunity Nexus and Cancer Immunotherapy

James C Lee1,2, Michael D Green3,4, Laura A Huppert1

  • 1Divisions of Hematology and Medical Oncology, Department of Medicine, University of California San Francisco, San Francisco, California.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 21, 2021
PubMed

Insights

Liver metastases reduce the effectiveness of immune checkpoint inhibitors by generating suppressive macrophages that eliminate CD8+ T cells. This immunosuppression also involves regulatory T-cell activation, impacting cancer treatment outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Translational Medicine

Background:

  • Liver metastases are increasingly recognized to impact cancer treatment efficacy.
  • Immune checkpoint inhibitors (ICIs) like pembrolizumab show reduced effectiveness in patients with liver metastases.
  • Recent studies investigate the mechanisms behind this observed phenomenon.

Purpose of the Study:

  • To review the literature on liver immune function and its role in ICI resistance.
  • To elucidate the mechanistic basis of immunosuppression caused by liver metastases.
  • To discuss potential interventions to overcome liver-mediated immune suppression.

Main Methods:

  • Literature review of clinical and translational studies.
  • Analysis of mechanistic observations from animal models (MC38 model).
  • Examination of immune cell populations, including CD11b+ macrophages and CD8+ T cells.

Main Results:

  • Liver metastases induce CD11b+ suppressive macrophages that mediate CD8+ T cell deletion via FasL.
  • Regulatory T-cell (Treg) activation contributes to systemic immunosuppression.
  • Pembrolizumab and other PD-1/PD-L1 inhibitors show diminished efficacy in cancers with liver involvement.

Conclusions:

  • Liver metastases create a profoundly immunosuppressive microenvironment.
  • Targeting liver-derived immunosuppression is crucial for improving ICI therapy in metastatic cancer.
  • Interventions like radiation, combination blockade, and Treg depletion may restore anti-tumor immunity.

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