Chronic lymphocytic leukemia cells increase neutrophils survival and promote their differentiation into CD16^highCD62L^dim immunosuppressive subset

Abstract

Reprogramming of neutrophils by malignant cells is well-described for many types of solid tumors, but data remain scarce for hematological diseases. Chronic lymphocytic leukemia (CLL) is characterized for a deep immune dysregulation mediated by leukemic cells that compromises patient's outcome. Murine models of CLL highlight the relevance of myeloid cells as tumor-driven reprogramming targets. In our study, we evaluated neutrophil reprogramming by CLL cells. We first show that the proportion of the CD16 CD62L neutrophil subset in peripheral blood of CLL patients is increased compared to age-matched healthy donors (HD). In vitro, neutrophils from HD cultured in the presence of CLL cells or conditioned media (CM) from CLL cells exhibited a longer lifespan. Depletion of G-CSF and GM-CSF from CM partially reversed the protective effect. In addition, the proportion of viable neutrophils that displayed a CD16 CD62L phenotype was increased in the presence of CM from CLL cells, being TGF-β/IL-10 responsible for this effect. Altogether, our results describe a novel mechanism through which CLL cells can manipulate neutrophils.

MicroLet-7b Regulates Neutrophil Function and Dampens Neutrophilic Inflammation by Suppressing the Canonical TLR4/NF-κB Pathway

“…Using a nucleofection plasmid transfection protocol, the transfection efficiency in neutrophils is low (~5%), when evaluated two hours post-transfection ( 58 ). Researchers have attempted to overcome this limitation by introducing granulocyte-macrophage colony-stimulating factor (GM-CSF) in the culture medium ( 59 ), while use of the leukemia cell line HL-60 as an alternative model ( 60 ) or direct electroporation of neutrophils ( 61 ) represent additional approaches to overcome this problem. The limitation for HL-60 cells is that they cannot mimic all aspects of neutrophil biology, and the conclusion from our in vitro experiment is that HL-60 cells cannot fully mimic the in vivo environments.…”

Tumor-derived HMGB1 induces CD62Ldim neutrophil polarization and promotes lung metastasis in triple-negative breast cancer

“…CD62L dim neutrophils are thought to be an independent subset due to their unique transcriptional properties in response to acute inflammation 36 , while another study illustrated their poor antimicrobial activity 37 . However, scholars in different fields have reported that CD62L dim neutrophils present as an immunosuppressive subset that promotes disease progression, especially in chronic lymphocytic leukemia 22 , 38 , 39 . In contrast, the literature suggests that CD62L dim neutrophils are associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) 40 .…”

“…The heterogeneity of neutrophils has been well shown, with identified cell types such as the tumor-killing N1 neutrophils, tumor-promoting N2 neutrophils, low-density neutrophils (LDNs) and high-density neutrophils (HDNs) 20 , 21 . In addition, some studies have shown that tumor cells in chronic lymphocytic leukemia promote neutrophil differentiation into the CD62L dim phenotype, which exerts immunosuppressive functions 22 . However, the influence of these processes on the changes and effects on tumor metastases have not yet been reported.…”

Neutrophil Diversity in Health and Disease

“…In another study of colorectal cancer patients receiving any form of cancer therapy, the expression of CD38 was increased in circulating neutrophils relative to untreated patients and healthy donors [114]. In chronic lymphocytic leukemia, leukemic lymphocytes promoted the ex vivo differentiation of neutrophils into a more immunosuppressive population, characterized as CD16 high CD62L dim , compared with neutrophils that were not exposed to these cells or their conditioned media [115]. Finally, two distinct neutrophil populations of CD13 high and CD13 low neutrophils, that are present both in blood and tumor tissues, were described in patients with pancreatic ductal adenocarcinoma (PDAC) [116], whereas two different circulating neutrophil populations were found based on the differential expression of immunoglobulin-like transcript 3 (ILT3)high and lowin NSCLC patients [117].…”