CD39 DELINEATES CELL EXHAUSTION IN MOUSE AND HUMAN TUMOR-ASSOCIATED CD8+ T CELLS: A POSSIBLE IMMUNOMODULATORY ROLE OF A ?DYSFUNCTIONAL? CELL SUBSET

CANALE, FERNANDO P.; RAMELLO, MARIA CECILIA; NUÑEZ, NICOLAS; ARAUJO FURLAN, CINTIA; GOROSITO SERRAN, MELISA; TOSELLO BOARI, JIMENA; BOSSIO, SABRINA N.; DEL CASTILLO, ANDRÉS; LEDESMA, MARTA; CHRISTINE SEDLIK; PIAGGIO, ELIANE; GRUPPI ADRIANA; ACOSTA RODRIGUEZ E V; MONTES CAROLINA L

Mar del Plata

Congreso; LXIV Reunión científica anual de la Sociedad Argentina de Inmunología, en conjunto con la reunión anual de SAIC y SAFE.; 2016

Sociedad Argentina de Inmunología, en conjunto con la reunión anual de SAIC y SAFE.

001 (892) CD39 DELINEATES CELL EXHAUSTION IN MOUSEAND HUMAN TUMOR-ASSOCIATED CD8+ T CELLS: APOSSIBLE IMMUNOMODULATORY ROLE OF A ?DYSFUNCTIONAL?CELL SUBSETFernando Pablo Canale1, María Cecilia Ramello1, NicolásNúñez2, Cintia Liliana Araujo Furlan1, Melisa GorositoSerrán1, Jimena Tosello Boari1, Sabrina Noemí Bossio1,Andrés Del Castillo3, Marta Ledesma3, Christine Sedlik2,4,Eliane Piaggio2,4, Adriana Gruppi1, Eva Virginia AcostaRodríguez1, Carolina Lucía Montes1.1Centro de Investigaciones en Bioquímica Clínica e Inmunología(CIBICI-CONICET), Departamento de BioquímicaClínica, Facultad de Ciencias Químicas, Universidad Nacionalde Córdoba, Haya de la Torre y Medina Allende,Ciudad Universitaria, Córdoba, Argentina. 2Institut Curie,PSL Research University, INSERM U932, F-75005, Paris,France. 3Hospital Rawson, Av. Gdor Amadeo Sabattini2025, Polo Sanitario, Córdoba, Argentina. 4Centre d?InvestigationClinique Biothérapie CICBT 1428, Institut Curie,Paris, F-75005 France.Tumor-infiltrating CD8+ T lymphocytes (CD8+ TILs) are crucialto eliminate tumors through cytotoxicity and cytokine production.Cancer cells blunt this process developing a microenvironment thatinduces dysfunctional and regulatory T cells. Here, we aimed tostudy by flow cytometry the expression of the immunomodulatoryecto-enzyme CD39 on CD8+ T cells in the context of anti-tumorresponse. Studying B16F10-OVA and other mouse cancer models,we defined three subsets: CD39-, CD39int and CD39high CD8+ Tcells, being the latter predominant in tumors but absent in lymphoidorgans (p≤0.0001). Of note, the frequency of CD39high CD8+TILs increased with tumor growth (p≤0.0001). CD39high CD8+TILs exhibited an exhausted phenotype with lower production ofTNF (p≤0.001) and IL-2 (p≤0.01) than CD39-/CD39int CD8+TILs, and higher expression of inhibitory receptors (PD-1, Tim-3,LAG-3, TIGIT and 2B4) (p≤0.0001 for all). Murine exhaustedCD8+ T cells displayed high ability to hydrolyze extracellular ATPin vitro, indicating that CD39 is enzymatically active on thesecells. Moreover, co-culture experiments showed that exhaustedCD8+ TILs are able to reduce IFNã production by conventionalCD8+ T cells (p≤0.05). Interestingly, in samples from 29 breastcancer and 4 melanoma patients we observed that CD39+ CD8+T cells were present in tumors and increased in invaded/metastaticlymph nodes compared to non-invaded lymph nodes (p≤0.001),while absent in peripheral blood. These cells exhibited impairedproduction of IFNã (p≤0.001), TNF (p≤0.01) and IL-2 (p≤0.05in lymph nodes) when compared to CD39- CD8+ T cells, andhigher expression of PD-1 (p≤0.01), TIGIT (p≤0.01) and BTLA(p≤0.05). These findings suggest that beside the loss of effectorfunctions, the tumor environment also drives the acquisition ofregulatory molecules on CD8+ T cells. CD39 may emerge notonly as a marker of CD8+ T cell dysfunction but also as a possibletarget for treatments aimed to restore anti-tumor immunity.