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+CD26high 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 CD26negCD8+ T cells are mainly transitional, effector memory and effectors, CD26lowCD8+ T cells are mainly naïve, stem cell, and central memory but CD26high T cells are differentiated to transitional and effector memory. CD26+CD8+ T cells are significantly reduced in CLL patients versus HCs. CD26high cells are enriched with Mucosal Associated Invariant T (MAIT) cells co-expressing CD161TVα7.2 and IL-18Rα. Also, CD26high 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. CD26high and CD26low T cells exhibit significantly lower frequencies of CD160, 2B4, TIGIT, ICOS, CD39, and PD-1 but higher levels of CD27, CD28, and CD73 versus CD26neg cells. To understand the mechanism linked to CD26high 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 CD26high 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 CD26highCD8+ T cells in CLL.

Systematic analysis of mucosal‐associated invariant T cells in haematological malignancies

“…Given the fact that the high expression of CD26 and expression of CD8 is a commonly observed phenotype of MAIT cells and that MAIT cells are predominant in CD8 + CD26 high T-cell subset, the findings presented in this study suggest that MAIT cells are also depleted in the setting of CLL. 28,29 Our study, the first to analyse a broad spectrum of haematological malignancies, implies that the decline of circulating MAIT cells can be considered a general phenomenon in patients with haematological malignancies. Their absolute amount and percentage among the T-cells were decreased when the whole group of haematological patients was compared with the healthy volunteers.…”

“…should be considered, as it describes the decrease of circulating CD8 + CD26 high T‐cells in peripheral blood of patients with CLL. Given the fact that the high expression of CD26 and expression of CD8 is a commonly observed phenotype of MAIT cells and that MAIT cells are predominant in CD8 + CD26 high T‐cell subset, the findings presented in this study suggest that MAIT cells are also depleted in the setting of CLL 28,29 …”

Transcriptomic profiling of peripheral blood cells in HPV‐associated carcinoma patients receiving combined valproic acid and avelumab

“…Multiplex analyses of plasma cytokines/chemokines were conducted by Mesoscale Discovery (MSD) kits, as we have reported before [ 45 , 46 ]. Data were obtained on a V‐plex® Sector Imager 2400 plate reader and analyzed on the msd workbench 3.0 software (MSD, Rockville, MD, USA).…”

Mucosal-associated invariant T cells in hematological malignancies: Current knowledge, pending questions

“…Finally, patients with chronic lymphocytic leukemia (CLL) harbored decreased numbers of circulating CD8+CD26hi T cells ( 15 ). It was already shown that MAIT cells express high levels of CD26 ( 13 , 16 ), and the authors confirmed the predominance of MAIT cells within the CD8+CD26hi subset.…”

“…No study to date has studied MAIT cells exhaustion in the context of hematologic malignancies. However, as already mentioned, MAIT cells are numerically deficient in patients with MM and AML ( 12 , 13 ); the reason for this is still obscure but one possibility would be that MAIT suffer from increased apoptosis ( 15 ). This would represent some kind of immune escape as well.…”