CD39 expression on CD8+ Tumor-infiltrating T cells is associated to effector memory phenotype and metabolic stress.

BOSSIO S; CONDAT F; ACOSTA RODRIGUEZ E; ABRATE C; MONTES CL; CANALE F; GRUPPI A

Mar del Plata

Congreso; LXVI Reunión Anual de la Sociedad Argentina de Inmunología; 2018

SAI

Previously we have demonstrated that exhausted tumor-infiltrating CD8+ T cells (TILs) exhibit high expression of the ecto-nucleotidase CD39. In this work we aimed to characterize the phenotype of the CD39+ TILs. Using the B16-F10-OVA cancer model we determined by FACS that CD8+CD39high TILS exhibited an effector memory phenotype (CD62L-CD44+), while CD8+CD39-TIls represent a heterogeneous population (central memory, effector memory and naïve). CD8+CD39high TILS showed higher frequency of KLRG-1+CD127- cells (short-live effector phenotype) than CD39low CD8+TILS (p≤0,05). In addition, we observed that CD8+CD39high TILs showed higher expression of CD8α than CD39- or CD39int CD8TILs (p≤0,0001 in both cases). In spleen and lymph node, CD39int CD8+T cells showed higher CD8α expression than CD39- cells. Similar results were observed in other cancer models like 4T1, MCA-OVA and CT26. We also evaluated markers of metabolic stress and we detected that CD8+CD39high TILS (obtained ex vivo) exhibited higher expression of p-mTOR, pS6 and p-AMPK than CD8+CD39-TILS (p≤0,005, p≤0,0001 and p≤0,001 respectively). After αCD3/αCD28 stimulation CD8+CD39highTILs showed lower expression of pmTOR and PS6 than CD8+CD39-TILs (p≤0,05). Studying breast cancer patients we observed that high frequency of CD8+CD39+ T cells from tumor or metastatic lymph node (MLN) showed a memory effector phenotype. Most of CD8+CD39- TILs cells exhibited phenotype of central memory or effector memory while in MLN most of this population correspond to naïve phenotype. CD8+CD39+ TILs showed higher expression of CD8α than CD39- TILs (p≤0,05). All together or results demonstrated that expression of CD39 on CD8+ T cells is associated to a short-live effector phenotype and metabolic stress. CD39 emerges as a target for treatments aimed to restore CD8 T cells anti-tumor immunity.