Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the
Fabienne McClanahan1, John C Riches2, Shaun Miller2
1Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Department of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;
Abstract:
T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the Emicro-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in the spleen. CD3(+)CD8(+) T cells from leukemic and aging healthy mice highly expressed PD-1, identifying aging as a confounder, but adoptive transfer experiments demonstrated CLL-specific PD-1 induction. Direct comparisons of PD-1 expression and function between aging CLL mice and controls identified PD-1(+) T cells in CLL as a heterogeneous population with variable effector function. This is highly relevant for therapeutic targeting of CD8(+) T cells, showing the potential of reprogramming and selective subset expansion to restore antitumor immunity.
Insights
Chronic lymphocytic leukemia (CLL) impairs T-cell function via PD-1/PD-L1 signaling. Aging confounds these effects, but CLL-specific T-cell changes offer therapeutic potential for restoring antitumor immunity.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Chronic lymphocytic leukemia (CLL) is characterized by T-cell dysfunction and immune suppression.
- PD-1/PD-L1 inhibitory signaling is a key mechanism of immunosuppression in CLL.
- The impact of microenvironments and aging on T-cell dysfunction in CLL is not well understood.
Purpose of the Study:
- To investigate T-cell dysfunction and PD-1/PD-L1 interactions in a mouse model of CLL.
- To differentiate CLL-specific T-cell changes from those induced by aging.
- To explore therapeutic strategies for restoring antitumor immunity in CLL.
Main Methods:
- Utilized the Emicro-TCL1 mouse model to longitudinally study T-cell phenotype and function in developing CLL.
- Analyzed PD-1 and PD-L1/PD-L2 expression in various organs.
- Employed adoptive transfer experiments to confirm CLL-specific PD-1 induction.
- Compared PD-1 expression and function in aging CLL mice and controls.
Main Results:
- CLL development significantly altered T-cell phenotype and function across all organs.
- Murine CLL cells exhibited high PD-L1 and PD-L2 expression, particularly in the spleen.
- Aging mice showed increased PD-1 expression on T cells, but adoptive transfer confirmed CLL-specific PD-1 induction.
- PD-1(+) T cells in CLL were heterogeneous, with variable effector functions.
Conclusions:
- Aging is a confounding factor in assessing T-cell dysfunction in CLL.
- CLL induces specific T-cell changes, including heterogeneous PD-1 expression with variable effector function.
- Targeting PD-1/PD-L1 interactions and selective T-cell subset expansion holds promise for restoring antitumor immunity in CLL.
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