CD39-CD73-adenosine effects in Sézary syndrome

In this issue of Blood, Yakymiv et al¹ provide evidence that malignant CD4+ T-cells derived from patients with Sézary syndrome (SS), the leukemic variant of cutaneous T-cell lymphoma (CTCL), express high levels of the CD39 and CD73 ectonucleotidases, which may contribute to an immunosuppressive microenvironment. Treatment of advanced stages of CTCLs remains challenging, reflecting a low rate of durable remissions despite recent approval of several targeted therapies, such as brentuximab and mogamulizumab. Unlike mature nodal T-cell malignancies, CTCLs derived from skin-homing memory CD4+ T-cells have very high tumor mutational burden due to ultraviolet radiation,² but responses to checkpoint inhibition remain modest.³ This level of response reflects the difficulty of enhancing T-cell immune responses in T-cell malignancy, and so an understanding of the tumor microenvironment in CTCLs remains a critical need.

Specifically, Yakymiv et al show that SS patients with high expression of CD39 have higher plasma levels of adenosine monophosphate (AMP) in vivo, compared to those of healthy donors, and when these CD39+ tumor cells are co-cultured in vitro with human pulmonary microvascular endothelial cells, increased concentrations of adenosine are generated. Furthermore, they report that CD3/CD28-mediated proliferation of CD8+ T-cells from SS patients and healthy donors is inhibited in the presence of adenosine triphosphate (ATP). In contrast, when inhibitors of the adenosine receptor (A2AR) are added, ATP does not inhibit proliferation of CD8+ T-cells. Although Yakymiv and colleagues did not analyze the effects of ATP on the proliferation of CD4+ malignant T-cells, Sonigo et al showed that both anti-CD73 antibody and A2AR inhibition only partially restored proliferation of the CD4+ malignant T-cells from SS patients.⁴ These results, albeit in a small cohort of SS patients, are compelling and suggest that the CD39/CD73/adenosine axis promotes immunosuppression in SS, enhancing our understanding of the tumor microenvironment in CTCL (see figure).

CD39 and CD73 are members of a family of ectonucleotidases that are expressed in a wide range of cancers to promote a favorable tumor microenvironment.⁵ In both solid and hematologic malignancies, extracellular ATP accumulates at levels much higher than those observed in healthy tissues, owing to tumor cell death and metabolic stress.⁶ Extracellular ATP acts as a danger signal, triggering proinflammatory responses, but CD39 hydrolyzes ATP to AMP, which is sequentially converted by CD73 into immunosuppressive adenosine, allowing the tumor to evade immune monitoring. Adenosine may affect the tumor microenvironment directly or by exosome-mediated cellular exchange of CD39. Other ectonucleotidases include CD38, CD157, and CD203a, which also generate adenosine via the sequential catabolism of NAD+. Although high expression of CD39 was initially characterized as a distinguishing feature of Treg cells, mediating their immunosuppressive abilities,⁷ many immune effector cells express CD39, including memory CD4+ T-cells with an exhausted phenotype that is recognized as a feature of SS cells. The bioavailability of adenosine is regulated by adenosine deaminase, and the docking station for adenosine deaminase is CD26, which intriguingly is consistently lost on malignant CD4+ T-cells in SS.

Functional studies have established a role for the CD39/CD73/adenosine pathway in other hematologic malignancies, notably chronic lymphocytic leukemia, which includes a plethora of effects on regulation of cellular components of the immune system to ensure maintenance of tolerance as well as effects on chemotaxis to enable tumor cells to be retained in growth-supportive niches.⁸ Other effects include upregulation of anti-apoptotic mediators, inhibition of cytotoxic T-cell activation and proliferation, and enhanced expression of checkpoint inhibitors such as programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).⁵ 

The reports of Yakymiv et al¹ and Sonigo et al⁴ have shown that increased expression of CD39 is found on the malignant CD4+ T-cells in SS patients, but larger studies are now required to clarify whether CD39 expression could represent a prognostic biomarker. Important to note is that these studies need to correlate expression of CD39 with genotype, as the A allele of the single-nucleotide polymorphism rs7096317 has been shown to be permissive for CD39 expression in healthy CD4+ T-cells,⁹ and CD39 expression also increases with age.¹⁰ Also important is an understanding of the spatial expression and function of CD39/CD73 in the skin as the tumor niche, as well as the direct effects of adenosine on the malignant T-cells, and specifically, whether adenosine contributes to the development of an exhausted phenotype in SS.

The CD39/CD73/adenosine pathway represents a promising therapeutic target, and indeed, clinical trials are in development using antibodies against both CD39 and CD73 and small molecule inhibitors of CD73.⁵ Trials assessing use of these novel agents in combination with chemotherapy, with radiotherapy, and with checkpoint inhibitors are also being considered.⁵ Mogamulizumab targeting the skin-homing chemokine receptor CCR4 expressed in CTCL was recently approved and provides a further potential combination approach targeting the malignant T-cell in CTCL with enhanced immune responses in the tumor microenvironment.

Conflict-of-interest disclosure: The authors declare no competing financial interests.