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Autocrine Adenosine Regulates Tumor Polyfunctional CD73+CD4+ Effector T Cells Devoid of Immune Checkpoints

Nicolas Gourdin1,2,3, Marion Bossennec1,2, Céline Rodriguez1,2,3

  • 1Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.

Cancer Research
|March 22, 2018
PubMed

Insights

Regulatory T cells (Tregs) expressing CD39 target CD73+ T effector cells (Teffs), inhibiting their IL17A secretion. This Treg activity blunts antitumor immunity, suggesting CD73+ Teffs as a potential therapeutic target.

Area of Science:

  • Immunology
  • Cancer Biology
  • T cell biology

Background:

  • Regulatory T cells (Tregs) and CD73-derived adenosine are implicated in anti-PD-1 therapy resistance.
  • Human Tregs express CD39 but not CD73, while CD73 defines a subset of polyfunctional CD4+ T effector cells (Teffs).

Purpose of the Study:

  • To investigate the interaction between CD39+ Tregs and CD73+ Teffs in the tumor microenvironment.
  • To determine the functional consequences of this interaction on antitumor immunity.

Main Methods:

  • Flow cytometry to analyze T cell populations and marker expression (CD39, CD73, CXCR3, CCR6, MDR1).
  • Assessment of cytokine production (IL17A, IFNγ, IL22, GM-CSF) by Teffs.
  • Measurement of ATP degradation and ATPase activity.

Main Results:

  • CD39+ Tregs selectively targeted CD73+ Teffs, degrading ATP into adenosine and inhibiting IL17A secretion.
  • Tumor-infiltrating CD73+ Teffs in breast and ovarian cancers were functionally impaired by Tregs with high CD39 and ATPase activity.
  • Tumor-infiltrating CD73+ Teffs lacked other immune checkpoints, suggesting selection under immune checkpoint blockade therapy.

Conclusions:

  • CD39+ Tregs suppress antitumor immunity by targeting CD73+ Teffs.
  • CD73+ Teffs represent a potential nonredundant target for restoring antitumor immunity in cancer patients.

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