Chronic lymphocytic leukemia

Control of chronic lymphocytic leukemia development by clonally-expanded CD8+ T-cells that undergo functional exhaustion in secondary lymphoid tissues

Abstract

Chronic lymphocytic leukemia (CLL) is associated with substantial alterations in T-cell composition and function. However, the role of T-cells in CLL remains largely controversial. Here, we utilized the Eµ-TCL1 mouse model of CLL as well as blood and lymph node samples of CLL patients to investigate the existence of anti-tumoral immune responses in CLL, and to characterize involved immune cell populations. Thereby, we identified an oligoclonal CD8+ effector T-cell population that expands along with CLL progression and controls disease development. We further show that a higher percentage of CD8+ effector T-cells produces IFNγ, and demonstrate that neutralization of IFNγ results in faster CLL progression in mice. Phenotypical and functional analyses of expanded CD8+ effector T-cells show significant differences in disease-affected tissues in mice, with cells in secondary lymphoid organs harboring hallmarks of activation-induced T-cell exhaustion. Notably, we further describe a respective population of exhausted CD8+ T-cells that specifically accumulate in lymph nodes, but not in peripheral blood of CLL patients. Collectively, these data emphasize the non-redundant role of CD8+ T-cells in suppressing CLL progression and highlight their dysfunction that can be exploited as target of immunotherapy in this malignancy.

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Acknowledgements

This study was supported by the German José Carreras Foundation (R14/23) to MSe, by the Spanish Ministry of Economy and Competitiveness (SAF 15/31242 R) and the Generalitat de Catalunya (2017 SGR 1009) to DC, by an NCT 3.0 funding program (NCT3.0_2015.13 ImmunOmics, NCT3.0_2015.2 SPL/RP) to MSch and RG, by the DFG (SFB1074 project B1) to StSt, and the BMBF-Network “PRECiSe” (031L0076A) and the ERA-NET TRANSCAN-2 program JTC 2014–project FIRE-CLL to StSt, PL and MSe, PMR was supported by the German Cancer Aid grant number 112069. We would like to thank Daniel Mertens, University of Ulm, for constant support and scientific discussions.

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Correspondence to Bola S. Hanna or Martina Seiffert.

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Hanna, B.S., Roessner, P.M., Yazdanparast, H. et al. Control of chronic lymphocytic leukemia development by clonally-expanded CD8+ T-cells that undergo functional exhaustion in secondary lymphoid tissues. Leukemia 33, 625–637 (2019). https://doi.org/10.1038/s41375-018-0250-6

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