Contrasting Immunopathogenic and Therapeutic Roles of Granulocyte Colony-Stimulating Factor in Cancer

Abstract

Tumor cells are particularly adept at exploiting the immunosuppressive potential of neutrophils as a strategy to achieve uncontrolled proliferation and spread. Recruitment of neutrophils, particularly those of an immature phenotype, known as granulocytic myeloid-derived suppressor cells, is achieved via the production of tumor-derived granulocyte colony-stimulating factor (G-CSF) and neutrophil-selective chemokines. This is not the only mechanism by which G-CSF contributes to tumor-mediated immunosuppression. In this context, the G-CSF receptor is expressed on various cells of the adaptive and innate immune systems and is associated with induction of T cell polarization towards the Th2 and regulatory T cell (Treg) phenotypes. In contrast to the potentially adverse effects of sustained, endogenous production of G-CSF by tumor cells, stringently controlled prophylactic administration of recombinant (r) G-CSF is now a widely practiced strategy in medical oncology to prevent, and in some cases treat, chemotherapy-induced severe neutropenia. Following an overview of the synthesis, structure and function of G-CSF and its receptor, the remainder of this review is focused on: (i) effects of G-CSF on the cells of the adaptive and innate immune systems; (ii) mechanisms by which this cytokine promotes tumor progression and invasion; and (iii) current clinical applications and potential risks of the use of rG-CSF in medical oncology.

T cells isolated from G-CSF-treated multiple myeloma patients are suitable for the generation of BCMA-directed CAR-T cells

“…Although many of the inhibitory actions of G-CSF on T cells are secondary effects caused by the regulation of other cell types, it has been reported that G-CSF directly controls T cell function. 25 , 33 To examine whether these direct effects impact anti-BCMA CAR-T cell activity, T cells were cultured for 3 days in the presence of recombinant G-CSF prior to activation, ARI2h CAR transduction, and cell expansion ( Figure 1 A). The efficacy of the recombinant G-CSF was tested by analyzing G-CSF-induced STAT3 phosphorylation in monocytes ( Figure S1 ).…”

“…It was important to study the effect of G-CSF in vivo , as well as in vitro , because G-CSF-mediated regulation of other immune cell types, such as dendritic cells, 40 monocytes, 41 and myeloid-derived suppressor cells (MDSCs), 42 also causes T cell suppression. 33 For example, increased MDSC mobilization to the peripheral blood promotes abnormalities in the T cell compartment, such as reduced proliferation and polarization of CD4 + cells from a Th1 phenotype towards a Th2 phenotype. 43 , 44 Moreover, the increased presence of histocompatibility leukocyte antigen DR isotype (HLA-DR) −/low CD33 + CD16 − MDSCs in peripheral blood causes T reg expansion, 44 highlighting the complex interplay between G-CSF and a wide range of immune cells.…”

Disseminated carcinomatosis of the bone marrow caused by granulocyte colony-stimulating factor: A case report and review of literature

“…Although the precise mechanism of DCBM as a manifestation of a metachronous recurrence of cured cancer is unclear, recent studies have indicated the reactivation of dormant DTCs by various factors, which are mainly related with angiogenesis and the immunologic antitumor surveillance system[ 19 - 23 ]. The administration of G-CSF has been reported to be one of the factors that can promote cancer progression and invasion in various cancers[ 24 ], and this interaction was confirmed in vivo using gastric cancer cells expressing G-CSFR[ 25 ]. However, previous clinical documentations have seldom documented that G-CSF could trigger recurrence of cured malignancies.…”

Effects of Prophylactic Administration of Granulocyte Colony-Stimulating Factor on Peripheral Leukocyte and Neutrophil Counts Levels After Chemotherapy in Patients With Early-Stage Breast Cancer: A Retrospective Cohort Study

“…However, no significant difference was detected for the incidence of leukopenia and neutropenia 12 months after chemotherapy between the long-acting and the short-acting groups. PEG-rhG-CSF and rhG-CSF have the same mechanism of action: G-CSF binds to G-CSF receptors expressed on hematopoietic cells to stimulate the proliferation of hematopoietic progenitor cells and accelerate the transformation of immature metamyelocytes into mature neutrophils, thereby increasing functional neutrophils in circulating peripheral blood ( 46 , 47 ). Compared with rhG-CSF, PEG-rhG-CSF can decrease plasma clearance and prolong half-life ( 15 ).…”