In this 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 with their CD39– counterparts) produced significantly lower IFN- 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.

Genetically-driven CD39 expression shapes human tumor-infiltrating CD8+ T cell functions / Gallerano, Daniela; Ciminati, Selina; Grimaldi, Alessio; Piconese, Silvia; Cammarata, Ilenia; Focaccetti, Chiara; Pacella, Ilenia; Accapezzato, Daniele; Lancellotti, Francesco; Sacco, Luca; Caronna, Roberto; Melaiu, Ombretta; Fruci, Doriana; D'Oria, Valentina; Manzi, Emy; Sagnotta, Andrea; Parrino, Chiara; Coletta, Diego; Peruzzi, Giovanna; Terenzi, Valentina; Battisti, Andrea; Cassoni, Andrea; Fadda, Maria Teresa; Brozzetti, Stefania; Fazi, Katia; Grazi, Gian Luca; Valentini, Valentino; Chirletti, Piero; Polimeni, Antonella; Barnaba, Vincenzo; Timperi, Eleonora. - In: INTERNATIONAL JOURNAL OF CANCER. - ISSN 0020-7136. - 147:9(2020), pp. 2597-2610. [10.1002/ijc.33131]

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

Gallerano, Daniela
Primo
;
Grimaldi, Alessio;Piconese, Silvia;Cammarata, Ilenia;Pacella, Ilenia;Accapezzato, Daniele;Caronna, Roberto;Manzi, Emy;Sagnotta, Andrea;Parrino, Chiara;Coletta, Diego;Peruzzi, Giovanna;Terenzi, Valentina;Battisti, Andrea;Cassoni, Andrea;Fadda, Maria Teresa;Brozzetti, Stefania;Valentini, Valentino;Chirletti, Piero;Polimeni, Antonella;Barnaba, Vincenzo
Penultimo
;
Timperi, Eleonora
Ultimo
2020

Abstract

In this 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 with their CD39– counterparts) produced significantly lower IFN- 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.
CD39; CD39 modulators; CD8+ TILs; SNP; checkpoint inhibitors
01 Pubblicazione su rivista::01a Articolo in rivista
Genetically-driven CD39 expression shapes human tumor-infiltrating CD8+ T cell functions / Gallerano, Daniela; Ciminati, Selina; Grimaldi, Alessio; Piconese, Silvia; Cammarata, Ilenia; Focaccetti, Chiara; Pacella, Ilenia; Accapezzato, Daniele; Lancellotti, Francesco; Sacco, Luca; Caronna, Roberto; Melaiu, Ombretta; Fruci, Doriana; D'Oria, Valentina; Manzi, Emy; Sagnotta, Andrea; Parrino, Chiara; Coletta, Diego; Peruzzi, Giovanna; Terenzi, Valentina; Battisti, Andrea; Cassoni, Andrea; Fadda, Maria Teresa; Brozzetti, Stefania; Fazi, Katia; Grazi, Gian Luca; Valentini, Valentino; Chirletti, Piero; Polimeni, Antonella; Barnaba, Vincenzo; Timperi, Eleonora. - In: INTERNATIONAL JOURNAL OF CANCER. - ISSN 0020-7136. - 147:9(2020), pp. 2597-2610. [10.1002/ijc.33131]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1407292
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