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Chronic lymphocytic leukemia presence impairs antigen-specific CD8⁺ T-cell responses through epigenetic reprogramming towards short-lived effectors.

ABSTRACT: T-cell dysregulation in chronic lymphocytic leukemia (CLL) associates with low response rates to autologous T cell-based therapies. How CLL affects antigen-specific T-cell responses remains largely unknown. We investigated (epi)genetic and functional consequences of antigen-specific T-cell responses in presence of CLL in vitro and in an adoptive-transfer murine model. Already at steady-state, antigen-experienced patient-derived T cells were skewed towards short-lived effector cells (SLEC) at the expense of memory-precursor effector cells (MPEC). Stimulation of these T cells in vitro showed rapid induction of effector genes and suppression of key memory transcription factors only in presence of CLL cells, indicating epigenetic regulation. This was investigated in vivo by following antigen-specific responses of naïve OT-I CD8⁺ cells to mCMV-OVA in presence/absence of TCL1 B-cell leukemia. Presence of leukemia resulted in increased SLEC formation, with disturbed inflammatory cytokine production. Chromatin and transcriptome profiling revealed strong epigenetic modifications, leading to activation of an effector and silencing of a memory profile through presence of CLL cells. Secondary challenge in vivo confirmed dysfunctional memory responses by antigen-experienced OT-I cells generated in presence of CLL. Altogether, we show that presence of CLL induces a short-lived effector phenotype and impaired memory responses by epigenetic reprogramming during primary responses.

SUBMITTER: Martens AWJ

PROVIDER: S-EPMC9851097 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Chronic lymphocytic leukemia presence impairs antigen-specific CD8<sup>+</sup> T-cell responses through epigenetic reprogramming towards short-lived effectors.

Martens Anne W J AWJ Kavazović Inga I Krapić Mia M Pack Su Min SM Arens Ramon R Jongejan Aldo A Moerland Perry D PD Eldering Eric E van der Windt Gerritje J W GJW Wensveen Felix M FM Peters Fleur S FS Kater Arnon P AP

Leukemia 20230119 3

T-cell dysregulation in chronic lymphocytic leukemia (CLL) associates with low response rates to autologous T cell-based therapies. How CLL affects antigen-specific T-cell responses remains largely unknown. We investigated (epi)genetic and functional consequences of antigen-specific T-cell responses in presence of CLL in vitro and in an adoptive-transfer murine model. Already at steady-state, antigen-experienced patient-derived T cells were skewed towards short-lived effector cells (SLEC) at the ...[more]

PMID: 36658390

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Project description: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+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.MethodsWe 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.ResultsCD26 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.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 CD26highCD8+ T cells in CLL.

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Chronic lymphocytic leukemia presence impairs antigen-specific CD8⁺ T-cell responses through epigenetic reprogramming towards short-lived effectors.

Publications

Chronic lymphocytic leukemia presence impairs antigen-specific CD8<sup>+</sup> T-cell responses through epigenetic reprogramming towards short-lived effectors.

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Chronic lymphocytic leukemia presence impairs antigen-specific CD8+ T-cell responses through epigenetic reprogramming towards short-lived effectors.

Publications

Chronic lymphocytic leukemia presence impairs antigen-specific CD8<sup>+</sup> T-cell responses through epigenetic reprogramming towards short-lived effectors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Chronic lymphocytic leukemia presence impairs antigen-specific CD8⁺ T-cell responses through epigenetic reprogramming towards short-lived effectors.