Characterisation of the tumour microenvironment in chronic lymphocytic leukemia by mass cytometry: implications for immunotherapy. (Doctoral thesis)

Chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults, is characterized by the accumulation of mature B lymphocytes in peripheral blood and lymphoid tissues. The progression of CLL and survival of malignant cells is highly dependent on complex interactions within the tumor microenvironment (TME) and despite recent advances in CLL treatment targeting the TME, CLL remains an incurable disease.
Therefore, we wanted to deeply characterize the immune landscape in the TME in murine and human CLL to identify novel potential targets for an immunotherapeutic approach. For this purpose, we performed a comprehensive and extensive characterization by high-dimensional mass cytometry to establish an extensive cartography of immune cell subsets. We demonstrated that relevant changes in the immune cell composition, especially the expansion of specific lymphoid and myeloid immune cell subsets, are associated with strong immune suppression thereby contributing to an escape phenotype in CLL. These CLL-associated changes can be restored in preclinical models by a dual PD1/LAG3 immune checkpoint blockade. Moreover, in human CLL, we demonstrated a high T cell heterogeneity between patients that can be stratified according to their T cell profile, and the correlation of specific T cell subsets with time to initial treatment, highlighting their potential prognostic value. In conclusion, with this first CyTOF study in CLL, we expanded the current knowledge of the phenotypic complexity of the TME. We demonstrated that dual targeting of immune checkpoints efficiently controlled CLL development in preclinical models and therefore could have potential benefits in CLL to restore a functional anti-tumor immunity.