Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukemia using patient similarity networks

Background: The tissue microenvironment in chronic lymphocytic leukemia (CLL) plays a key role in promoting neoplastic cell survival, proliferation, and drug resistance. There is a lack of complex characterization of CLL blood microenvironment and its clinical impact. Methods: Immunophenotypic profiles of circulating immune cells in 244 CLL patients (untreated, n=123; novel agents, n=67; previous immunochemotherapy, n=54) and age/sex-matched healthy controls (n=52) were assessed using flow cytometry and analyzed by multivariate patient similarity networks (PSNs). Results: Our study revealed high inter-individual heterogeneity in distribution and activation status of bystander immune cells in CLL, depending on the bulk of CLL cells. High CLL counts were associated with low activation status on circulating monocytes, T and NK cells and vice versa low CLL counts with high activation of immune cells, reaching levels in controls. Regarding treatment, the highest activation of immune cells, particularly of intermediate and non-classical monocytes, was evident in patients treated with novel agents. Clustering and visualization using PSNs confirmed low activation of immune cells in progressive disease, irrespectively of IgHV status and Binet stage. Calculating time-to-event endpoint, patients with high intermediate monocytes (>5.4%), predominantly low activated, were associated with 2.5-fold higher likelihood (95% CI 1.421-4.403, P =0.002) of event than those with low percentage of intermediate monocytes. Conclusions: Activation of circulating immune cells are dependent on the CLL cell counts and used therapy, with the lowest activation in patients with progressive disease. Percentage and activation of intermediate monocytes could be of prognostic value in CLL.