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ACKR4 restrains antitumor immunity by regulating CCL21

Carly E Whyte1, Maleika Osman1, Ervin E Kara1

  • 1Chemokine Biology Laboratory, Department of Molecular and Biomedical Science, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

The Journal of Experimental Medicine
|April 15, 2020
PubMed

Insights

Host atypical chemokine receptor 4 (ACKR4) limits anti-tumor CD8+ T cells in the tumor microenvironment. Blocking ACKR4 increases T cells, inhibits tumor growth, and may improve immunotherapy effectiveness.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Current immunotherapies show promise but face limitations in solid tumors due to low tumor-specific T cell presence.
  • The tumor microenvironment (TME) plays a critical role in regulating anti-tumor immune responses.
  • Understanding factors controlling T cell infiltration and activation in the TME is crucial for enhancing cancer treatments.

Purpose of the Study:

  • To investigate the role of atypical chemokine receptor 4 (ACKR4) in regulating intratumor T cell responses.
  • To determine the impact of ACKR4 on CD8+ T cell accumulation and activation within the tumor microenvironment.
  • To explore ACKR4 and CCL21 as potential therapeutic targets for improving cancer immunotherapy.

Main Methods:

  • Utilized mouse models to study the effects of ACKR4 deficiency on tumor growth and T cell infiltration.
  • Analyzed the expression and function of ACKR4 in nonhematopoietic cells within the TME.
  • Investigated the regulatory mechanisms of ACKR4 on dendritic cell retention and chemokine levels (CCL21) in tumors.

Main Results:

  • Absence of ACKR4 led to increased intratumor CD8+ T cells, which inhibited tumor growth.
  • Nonhematopoietic ACKR4 expression was essential for controlling T cell accumulation.
  • ACKR4 was found to inhibit CD103+ dendritic cell retention by regulating intratumor CCL21 levels.

Conclusions:

  • Host ACKR4 acts as a critical regulator limiting CD8+ T cell accumulation and activation in the tumor microenvironment.
  • ACKR4-mediated regulation of CCL21 influences dendritic cell retention and T cell infiltration.
  • Targeting ACKR4 and CCL21 presents a promising strategy to enhance the efficacy of immunotherapies like immune checkpoint blockade.

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