Depletion of polyfunctional CD26highCD8+ T cells repertoire in chronic lymphocytic leukemia

Abstract Background CD8 + T cells play an essential role against tumors but the role of human CD8 + CD26 + T cell subset against tumors, in particular, haematological cancers such as chronic lymphocytic leukemia (CLL) remains unknown. Although CD4 + CD26 high T cells are considered for adoptive cancer immunotherapy, the role of CD8 + CD26 + T cells is ill-defined. Therefore, further studies are required to better determine the role of CD8 + CD26 + T cells in solid tumors and haematological cancers. Methods We studied 55 CLL and 44 age-sex-matched healthy controls (HCs). The expression of CD26 on different T cell subsets (e.g. naïve, memory, effector, and etc.) was analyzed. Also, functional properties of CD8 + CD26 + and CD8 + CD26 − T cells were evaluated. Finally, the plasma cytokine/chemokine and Galectin-9 (Gal-9) levels were examined. Results CD26 expression identifies three CD8 + T cell subsets with distinct immunological properties. While CD26 neg CD8 + T cells are mainly transitional, effector memory and effectors, CD26 low CD8 + T cells are mainly naïve, stem cell, and central memory but CD26 high T cells are differentiated to transitional and effector memory. CD26 + CD8 + T cells are significantly reduced in CLL patients versus HCs. CD26 high cells are enriched with Mucosal Associated Invariant T (MAIT) cells co-expressing CD161TVα7.2 and IL-18Rα. Also, CD26 high cells have a rich chemokine receptor profile (e.g. CCR5 and CCR6), profound cytokine (TNF-α, IFN-γ, and IL-2), and cytolytic molecules (Granzyme B, K, and perforin) expression upon stimulation. CD26 high and CD26 low T cells exhibit significantly lower frequencies of CD160, 2B4, TIGIT, ICOS, CD39, and PD-1 but higher levels of CD27, CD28, and CD73 versus CD26 neg cells. To understand the mechanism linked to CD26 high depletion, we found that malignant B cells by shedding Galectin-9 (Gal-9) contribute to the elevation of plasma Gal-9 in CLL patients. In turn, Gal-9 and the inflammatory milieu (IL-18, IL-12, and IL-15) in CLL patients contribute to increased apoptosis of CD26 high T cells. Conclusions Our results demonstrate that CD26 + T cells possess a natural polyfunctionality to traffic and exhibit effector functions and resist exhaustion. Therefore, they can be proposed for adoptive cancer immunotherapy. Finally, neutralizing and/or inhibiting Gal-9 may preserve CD26 high CD8 + T cells in CLL.