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

Abstract

The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4 T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39 Tregs selectively targeted CD73 Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73 Teffs to secrete IL17A. CD73 Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73 Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity. Polyfunctional CD73 T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. .

MDR1 in immunity: friend or foe?

“…63 In addition, we showed an enrichment in MDR1-positive cells within CD4 + CD73 + Teff infiltrating breast and ovarian carcinomas (unpublished data) that secrete anti-tumor cytokines (IFNγ, IL-17A, TNFα) ex vivo in the absence of adenosine or ATP/AMP. 62 In addition, we evidenced that this specific subset expresses very low level of inhibitory immune checkpoints like PD-1 and CTLA-4. This highly polyfunctional CD73 + MDR1 + Teff population might therefore be of interest in therapeutic approaches combining MDR1-associated chemotherapy and anti-CD73 targeting therapy to avoid adenosine production and potentiate pro-inflammatory response of this specific subset.…”

“…61 Moreover, our team recently characterized, in human, the CD73 + Teff population that is particularly enriched in Th1.17 and expressed higher MDR1 levels than their CD73 neg counterpart. 62 A recent study also suggests that MDR1 is also selectively expressed by Teff bearing the lectin-like receptor CD161. 63 When analyzed in detail, it appears that this CD161 + Rh123 low (as a surrogate marker of MDR1) population has strong Th1.17 characteristics and that its high MDR1 expression could contribute to their long-term life span among virus-specific antigen memory T cell pool.…”

“…The Th1.17 subset expressing high MDR1 level and also secreting pro-inflammatory cytokines, 61,62 appears as an asset in the anti-tumor immune response in contrast to its deleterious impact in autoimmune diseases. In long term chemotherapy treated AML patients, the non-malignant CD4 + CD161 + MDR1 + T cells fraction is increased, and they conserve their anti-viral properties and display self-renewal capacities.…”

CD73 promotes tumor metastasis by modulating RICS/RhoA signaling and EMT in gastric cancer

“…Extensive research has reported that purinergic signaling is a crucial component of tumor microenvironments (TMEs) with therapeutic potential in solid tumors 8,9 . Purine or pyrimidine nucleotides, such as ATP, ADP, and adenosine in TMA, have been discovered as important signaling molecules that engaged different P1 nucleoside and P2 nucleotide receptors on cancer or stromal cells [10][11][12][13] . The complex network of purinergic signaling events plays a key role in immune escape and accelerated growth of cancer cells, and eventually metastasis.…”

Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma

“…To further characterize the T cell subpopulations, we analyzed the expression of the adenosine (ADO) producing ectonucleotidases CD39 and CD73, which can define a variety of regulatory cell populations [22,23,30]. CD4 + T h cells of the blood can be divided into three subpopulations based on their expression of CD39 and CD73: (I) CD39 + T reg , (II) activated CD73 + T h cells, and (III) double negative T h cells (Fig.…”