CD73 Ectonucleotidase Restrains CD8+ T Cell Metabolic Fitness and Anti-tumoral Activity

Abstract

CD39 and CD73 are ectoenzymes that dephosphorylate ATP into its metabolites; ADP, AMP, and adenosine, and thus are considered instrumental in the development of immunosuppressive microenvironments. We have previously shown that within the CD8+ T cell population, naïve and memory cells express the CD73 ectonucleotidase, while terminally differentiated effector cells are devoid of this enzyme. This evidence suggests that adenosine might exert an autocrine effect on CD8+ T cells during T cell differentiation. To study the possible role of CD73 and adenosine during this process, we compared the expression of the adenosinergic signaling components, the phenotype, and the functional properties between CD73-deficient and WT CD8+ T cells. Upon activation, we observed an upregulation of CD73 expression in CD8+ T cells along with an upregulation of the adenosine A2A receptor. Interestingly, when we differentiated CD8+ T cells to Tc1 cells in vitro, we observed that these cells produce adenosine and that CD73-deficient cells present a higher cytotoxic potential evidenced by an increase in IFN-γ, TNF-α, and granzyme B production. Moreover, CD73-deficient cells presented a increased glucose uptake and higher mitochondrial respiration, indicating that this ectonucleotidase restrict the mitochondrial capacity in CD8+ T cells. In agreement, when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more effective in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented lower levels of exhaustion markers than wild type cells. All these data suggest an autocrine effect of CD73-mediated adenosine production, limiting differentiation and cytotoxic T cells’ metabolic fitness.

Ecto-5′-Nucleotidase (CD73) Regulates the Survival of CD8+ T Cells

“…Moreover, CD73-deficient cells presented an increased glucose uptake and higher mitochondrial respiration, indicating that this ectonucleotidase restricts the mitochondrial capacity in CD8+ T cells. Finally, when adoptively transferred into tumor-bearing mice, CD73 deficient cells were more effective against the tumor and expressed lower levels of exhaustion markers (Briceño et al, 2021). All this data suggests that CD73 may act as a checkpoint inhibitor under antigenic stimulation, limiting effector differentiation and delaying cytotoxic T cells' metabolic reprogramming.…”

Identification of the Mouse T Cell ADP-Ribosylome Uncovers ARTC2.2 Mediated Regulation of CD73 by ADP-Ribosylation

“…CD8 + T cells play a critical role in anti-tumor immune responses. CD73 on CD8 T cells seems to significantly contribute to the anti-tumor immunity response, since adoptively transferred CD73-deficient ovalbumin-specific OT-I T cells were more potent in killing OVA-expressing B16 melanoma tumors compared to WT OT-I T cells ( 47 ). This was accompanied by lower expression levels of the exhaustion markers programmed cell death protein 1 (PD-1) and CD39, strengthening the role of CD73 as an immune checkpoint and as a potential target in tumor therapy.…”

Exosomes: Small EVs with Large Immunomodulatory Effect in Glioblastoma

“…The evidence is growing to also consider CD73 as a potential target [73]. For example, Briceño et al [74] recently published on the autocrine effect of CD73-mediated adenosine production, which limits the differentiation and metabolic fitness of CD8+ T cells. This finding has been supported by the fact that CD73-deficient cells, on the one hand, showed increased glucose uptake and higher mitochondrial respiration and, on the other hand, achieved a more effective reduction in tumor burden than wild-type cells after adoptive transfer into B16.OVA melanoma-bearing mice.…”