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Les lymphocytes T CD8 innés et immunosurveillance antitumorale : application au modèle de la leucémie myéloïde chronique

Abstract : We have recently identified a new subset of innate T cells in humans, which we have termed « innate CD8 T-cells ». These cells express TCRαβ along with the transcription factor Eomesodermine (Eomes) and KIR/NKG2A membrane receptors. Innate CD8 T-cells share functional and phenotypic features with “innate memory” CD8 T-cells discovered in mice in the early 2000s. The development of these cells depends on the secretion of IL-4 by the T cells expressing the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF), and particularly iNKT, also called « invariant Natural Killer T-cells ». We have used the physiopathological model of chronic myeloid leukemia (CML) to study the potential role of innate CD8 T -cells in anticancer immunity in humans. Indeed, CML is considered to be one of the cancers most sensitive to immunological manipulation. CML is a malignant hemopathy that belongs to the family of myeloproliferative neoplasms characterized by the presence of the BCR-ABL1 oncogene. This oncogene is responsible for expression of the oncoprotein BCR-ABL with deregulated tyrosine kinase activity. Tyrosine kinase inhibitors (TKI) represent the standard of care for CML patients, of which the first in class was Imatinib. This targeted therapy has dramatically improved outcomes CML patients' outcomes, but they cannot achieve a cure. We previously reported that iNKT lymphocytes, a sub-population of innate T cells of which the implication into anti-tumoral immunosurveillance has been clearly demonstrated in human and in mouse models, are anergic in CML patients at diagnosis. Although these cells are functionally impaired, particularly in terms of IL-4 secretion, we have shown that their functional deficiencies are totally restored in CML patients in complete cytogenetic remission upon Imatinib therapy. Similarly to the iNKT lymphocytes, we presently show a major defect in the innate CD8 T-cells during the chronic phase in CML patients compared to those of healthy donors (HD) or patients in major molecular remission (MMR). This numerical defect is associated with a loss of NK-like functions (interferon-γ expression after innate stimulation by IL-12+IL-18 cytokines and with a loss of degranulation after stimulation via CD16). Interestingly, we have observed in patients in MMR under Imatinib a numeric and functional restoration that is at least partial, in terms of interferon-γ secretion after innate stimulation, of the innate CD8 T-cells. In analysis of cohorts of HD, CML patients at diagnosis and those in MMR under TKI, we have observed a correlation between Eomes expression by innate T CD8 T-cells and PLZF expression by iNKT cells. This finding underscores a possible dynamic process of generation of innate CD8 T-cells in humans that would depend on iNKT cells, as is the case in mice. To test the hypothesis that innate CD8 T-cells contribute to the control of CML, we have analyzed their status in a cohort of CML patients who, in spite of a persistent minimal residual disease, had maintained remission (MMR) more than two years after TKI discontinuation. In these patients, we demonstrate a dramatic increase of functional active innate CD8 T-cells as compared to HD and patients in MMR under TKI. All in all, these results underscore the major role of innate CD8 T-cells in anti-leukemic immunity during CML disease. We believe and we will test the hypothesis that the numeric and functional restoration of this subset might constitute a potential biomarker of successful TKI cessation in CML. We will also investigate whether innate CD8 T-cells could be a target for immunotherapy-based strategy.
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Submitted on : Friday, May 7, 2021 - 3:01:38 AM
Last modification on : Wednesday, May 12, 2021 - 7:59:17 PM

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Emilie Cayssials. Les lymphocytes T CD8 innés et immunosurveillance antitumorale : application au modèle de la leucémie myéloïde chronique. Médecine humaine et pathologie. Université de Poitiers, 2020. Français. ⟨NNT : 2020POIT1407⟩. ⟨tel-03220105⟩

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