Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions.
Daniela GalleranoSelina CiminatiAlessio GrimaldiSilvia PiconeseIlenia CammarataChiara FocaccettiIlenia PacellaDaniele AccapezzatoFrancesco LancellottiLuca SaccoRoberto CaronnaOmbretta MelaiuDoriana FruciValentina D'OriaEmy ManziAndrea SagnottaChiara ParrinoDiego ColettaGiovanna PeruzziValentina TerenziAndrea BattistiAndrea CassoniMaria Teresa FaddaStefania BrozzettiKatia FazziGian Luca GraziValentino ValentiniPiero ChirlettiAntonella PolimeniVincenzo BarnabaEleonora TimperiPublished in: International journal of cancer (2020)
In our study, we investigated the role of CD39 on tumor-infiltrating CD8+ T lymphocytes (CD8+ TILs) in colorectal, head and neck and pancreatic cancers. Partially confirming recent observations correlating the CD39 expression with T-cell exhaustion, we demonstrated a divergent functional activity in CD39+ CD8+ TILs. On the one hand, CD39+ CD8+ TILs (as compared to their CD39- counterparts) produced significantly lower IFN-γ and IL-2 amounts, expressed higher PD-1, and inversely correlated with perforin and granzyme B expression. On the other, they displayed a significantly higher proliferative capacity ex vivo that was inversely correlated with the PD-1 expression. Therefore, CD39+ CD8+ TILs, including those co-expressing the CD103 (a marker of T resident memory [TRM] cells), were defined as partially dysfunctional T cells that correlate with tumor patients with initial progression stages. Interestingly, our results identified for the first time a single nucleotide polymorphism (SNP rs10748643 A>G), as a genetic factor associated with CD39 expression in CD8+ TILs. Finally, we demonstrated that compounds inhibiting CD39-related ATPases improved CD39+ CD8+ T-cell effector function ex vivo, and that CD39+ CD8+ TILs displayed effective suppression function in vitro. Overall these data suggest that the SNP analysis may represent a suitable predictor of CD39+ CD8+ T-cell expression in cancer patients, and propose the modulation of CD39 as a new strategy to restore partially exhausted CD8+ TILs.