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Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions.

International journal of cancer (2020-06-03)
Daniela Gallerano, Selina Ciminati, Alessio Grimaldi, Silvia Piconese, Ilenia Cammarata, Chiara Focaccetti, Ilenia Pacella, Daniele Accapezzato, Francesco Lancellotti, Luca Sacco, Roberto Caronna, Ombretta Melaiu, Doriana Fruci, Valentina D'Oria, Emy Manzi, Andrea Sagnotta, Chiara Parrino, Diego Coletta, Giovanna Peruzzi, Valentina Terenzi, Andrea Battisti, Andrea Cassoni, Maria Teresa Fadda, Stefania Brozzetti, Katia Fazzi, Gian Luca Grazi, Valentino Valentini, Piero Chirletti, Antonella Polimeni, Vincenzo Barnaba, Eleonora Timperi
ABSTRACT

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.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
Dulbecco′s Phosphate Buffered Saline, Modified, without calcium chloride and magnesium chloride, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
2-Mercaptoethanol, ≥99.0%
Sigma-Aldrich
DL-Dithiothreitol, ≥98% (HPLC), ≥99.0% (titration)
Sigma-Aldrich
Collagenase from Clostridium histolyticum, suitable for release of physiologically active rat hepatocytes, Type IV, 0.5-5.0 FALGPA units/mg solid, ≥125 CDU/mg solid
Sigma-Aldrich
Ethylenediaminetetraacetic acid disodium salt dihydrate, ACS reagent, 99.0-101.0%