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.
Gallerano, D., Ciminati, S., Grimaldi, A., Piconese, S., Cammarata, I., Focaccetti, C., Pacella, I., Accapezzato, D., Lancellotti, F., Sacco, L., Caronna, R., Melaiu, O., Fruci, D., D'Oria, V., Manzi, E., Sagnotta, A., Parrino, C., Coletta, D., Peruzzi, G., Terenzi, V., Battisti, A., Cassoni, A., Fadda, M. T., Brozzetti, S., Fazzi, K., Grazi, G. L., Valentini, V., Chirletti, P., Polimeni, A., Barnaba, V., Timperi, E., Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions, <<INTERNATIONAL JOURNAL OF CANCER>>, 2020; 147 (9): 2597-2610. [doi:10.1002/ijc.33131] [https://hdl.handle.net/10807/305299]
Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions
Timperi, Eleonora
2020
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.
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