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

BackgroundCD8(+) 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.MethodsWe studied 55 CLL and 44 age-sex-matched healthy controls (HCs). The expression of CD26 on different T cell subsets (e.g. naive, 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.ResultsCD26 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 naive, 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 CD161TV alpha 7.2 and IL-18R alpha. Also, CD26(high) cells have a rich chemokine receptor profile (e.g. CCR5 and CCR6), profound cytokine (TNF-alpha, IFN-gamma, 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.ConclusionsOur 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. Key messagesCD26highCD8+ cells as potential adoptive immunotherapy candidateCD26highCD8+ T cells are enriched with MAIT cellsGalectin-9 preferentially induces apoptosis in CD26highCD8+ T cellsMalignant B cells are a source of Galectin-9

Automated summary

This study found that CD26(+)CD8(+) T cells are reduced in chronic lymphocytic leukemia (CLL), but they possess polyfunctionality and durability, making them potential candidates for immunotherapy. Additionally, malignant B cells induce apoptosis of CD26(+)CD8(+) T cells through the release of Galectin-9.