TY - JOUR
T1 - Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions
AU - Gallerano, Daniela
AU - Ciminati, Selina
AU - Grimaldi, Alessio
AU - Piconese, Silvia
AU - Cammarata, Ilenia
AU - Focaccetti, Chiara
AU - Pacella, Ilenia
AU - Accapezzato, Daniele
AU - Lancellotti, Francesco
AU - Sacco, Luca
AU - Caronna, Roberto
AU - Melaiu, Ombretta
AU - Fruci, Doriana
AU - D'Oria, Valentina
AU - Manzi, Emy
AU - Sagnotta, Andrea
AU - Parrino, Chiara
AU - Coletta, Diego
AU - Peruzzi, Giovanna
AU - Terenzi, Valentina
AU - Battisti, Andrea
AU - Cassoni, Andrea
AU - Fadda, Maria Teresa
AU - Brozzetti, Stefania
AU - Fazzi, Katia
AU - Grazi, Gian Luca
AU - Valentini, Valentino
AU - Chirletti, Piero
AU - Polimeni, Antonella
AU - Barnaba, Vincenzo
AU - Timperi, Eleonora
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - CD39
KW - CD39 modulators
KW - checkpoint inhibitors
KW - SNP
KW - CD8+ TILs
KW - CD39
KW - CD39 modulators
KW - checkpoint inhibitors
KW - SNP
KW - CD8+ TILs
UR - http://hdl.handle.net/10807/305299
U2 - 10.1002/ijc.33131
DO - 10.1002/ijc.33131
M3 - Article
SN - 1097-0215
VL - 147
SP - 2597
EP - 2610
JO - International Journal of Cancer
JF - International Journal of Cancer
ER -