Proteomic and bioinformatic profiling of neutrophils in CLL reveals functional defects that predispose to bacterial infections

Abstract

Patients with chronic lymphocytic leukemia (CLL) typically suffer from frequent and severe bacterial infections. Although it is well known that neutrophils are critical innate immune cells facilitating the early defense, the underlying phenotypical and functional changes in neutrophils during CLL remain largely elusive. Using a murine adoptive transfer model of CLL, we demonstrate aggravated bacterial burden in CLL-bearing mice upon a urinary tract infection with uropathogenic Escherichia coli. Bioinformatic analyses of the neutrophil proteome revealed increased expression of proteins associated with interferon signaling and decreased protein expression associated with granule composition and neutrophil migration. Functional experiments validated these findings by showing reduced levels of myeloperoxidase and acidification of neutrophil granules after ex vivo phagocytosis of bacteria. Pathway enrichment analysis indicated decreased expression of molecules critical for neutrophil recruitment, and migration of neutrophils into the infected urinary bladder was significantly reduced. These altered migratory properties of neutrophils were also associated with reduced expression of CD62L and CXCR4 and correlated with an increased incidence of infections in patients with CLL. In conclusion, this study describes a molecular signature of neutrophils through proteomic, bioinformatic, and functional analyses that are linked to a reduced migratory ability, potentially leading to increased bacterial infections in patients with CLL.

ComplexEye - a multi lens array microscope for High-Throughput embedded immune cell migration analysis

“…This showed that deregulated neutrophil motility in AML patients normalized 3-4 weeks after transplantation (unpublished data). We also demonstrated that the severity of myelodysplastic syndromes was closely associated with the degree of migration depression in patient´s neutrophils 11 and migration defects were a hallmark of chronic myeloid leukemia 38 and atypical chronic myeloid leukemia 12 . Taken together these examples highlight the diagnostic potential of migration studies.…”

Identification of potential resistance mechanisms and therapeutic targets for the relapse of BCMA CAR-T therapy in relapsed/refractory multiple myeloma through single-cell sequencing

“…Two clusters of neutrophils increased at progression. Cluster 0 expressed many interferon-induced genes, such as ISG15, IRF1, ISG20, and more, which play a major role in the development and metastatic progression of cancers [ 93 , 94 ]. Cluster 4 expressed MMP8, which is mainly produced by neutrophils that can either inhibit or promote tumor progression in certain cancers [ 95 – 97 ].…”

Imaging innate immunity*

“…We have recently shown that the severity of myelodysplastic syndromes, a heterogeneous group of hematopoietic stem cell disorders with a tendency for leukemogenesis, can be very well predicted by measuring the degree of migration depression in peripheral neutrophils in vitro 146 . Furthermore, migration defects are a hallmark of neutrophils in chronic lymphocytic leukemia 147 and atypical chronic myeloid leukemia 148 . These are, however, just glimpses into what might be possible if we were able to routinely measure immune cell migration in clinically approved assays from patients.…”