Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer

Mehmeti-Ajradini, Meliha; Bergenfelz, Caroline; Larsson, Anna-Maria; Carlsson, Robert; Riesbeck, Kristian; Ahl, Jonas; Janols, Helena; Wullt, Marlene; Bredberg, Anders; Källberg, Eva; Gunnarsdóttir, Fríða Björk; Millrud, Camilla Rydberg; Rydén, Lisa; Paul, Gesine; Loman, Niklas; Adolfsson, Jörgen; Carneiro, Ana; Jirström, Karin; Killander, Fredrika; Bexell, Daniel; Leandersson, Karin

doi:10.26508/lsa.202000893

Cited by 16 publications

(11 citation statements)

References 60 publications

(118 reference statements)

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“…Neutrophils among TANs with proven immunosuppressive function have been extensively studied and have been named granulocytic myeloid-derived suppressor cells (G-MDSCs) or polymorphonuclear myeloid-derived suppressive cells. G-MDSCs appear as neutrophils at different stages of maturation [ 168 ]. G-MDSCs flexibly adapt to the cancer microenvironment.…”

Section: Neutrophil Plasticity and The Cancer Microenvironmentmentioning

confidence: 99%

Neutrophils in cancer carcinogenesis and metastasis

2021

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In recent years, neutrophils have attracted increasing attention because of their cancer-promoting effects. An elevated neutrophil-to-lymphocyte ratio is considered a prognostic indicator for patients with cancer. Neutrophils are no longer regarded as innate immune cells with a single function, let alone bystanders in the pathological process of cancer. Their diversity and plasticity are being increasingly recognized. This review summarizes previous studies assessing the roles and mechanisms of neutrophils in cancer initiation, progression, metastasis and relapse. Although the findings are controversial, the fact that neutrophils play a dual role in promoting and suppressing cancer is undeniable. The plasticity of neutrophils allows them to adapt to different cancer microenvironments and exert different effects on cancer. Given the findings from our own research, we propose a reasonable hypothesis that neutrophils may be reprogrammed into a cancer-promoting state in the cancer microenvironment. This new perspective indicates that neutrophil reprogramming in the course of cancer treatment is a problem worthy of attention. Preventing or reversing the reprogramming of neutrophils may be a potential strategy for adjuvant cancer therapy.

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Section: Neutrophil Plasticity and The Cancer Microenvironmentmentioning

confidence: 99%

Neutrophils in cancer carcinogenesis and metastasis

2021

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“…A single-cell transcriptomic analysis of the myeloid compartment in the splenocytes from two tumor-bearing mice (PyMT tumor model) and 2 tumor-free control animals has suggested that PMN-MDSCs differ from their normal myeloid counterparts and may originate from neutrophil progenitor cells undergoing an aberrant differentiation path ( 82 ). Data from another recent study have suggested that peripheral PMN-MDSCs from patients with metastatic breast cancer are more closely related to healthy donors’ neutrophils than to MDSCs induced in another pathological condition (Gram-positive sepsis) ( 85 ). Further mass-cytometry analysis revealed that unique subpopulations of these granulocytic cells were specifically present in cancer patients, with a majority of low density mature activated neutrophils and a minority of immature neutrophils lacking maturation markers (CD10, CD13, CD45) at different maturation stages.…”

Section: Immunosuppressive Myeloid Cells Of the Granulocytic Lineage:...mentioning

confidence: 99%

Beyond Immunosuppression: The Multifaceted Functions of Tumor-Promoting Myeloid Cells in Breast Cancers

Blaye

Boyer²,

Peyraud³

et al. 2022

Front. Immunol.

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Breast cancers are commonly associated with an immunosuppressive microenvironment responsible for tumor escape from anti-cancer immunity. Cells of the myeloid lineage account for a major part of this tumor-promoting landscape. These myeloid cells are composed of heterogeneous subsets at different stages of differentiation and have traditionally been described by their cardinal ability to suppress innate and adaptive anticancer immunity. However, evidence has accumulated that, beyond their immunosuppressive properties, breast cancer-induced myeloid cells are also equipped with a broad array of “non-immunological” tumor-promoting functions. They therefore represent major impediments for anticancer therapies, particularly for immune-based interventions. We herein analyze and discuss current literature related to the versatile properties of the different myeloid cell subsets engaged in breast cancer development. We critically assess persisting difficulties and challenges in unequivocally discriminate dedicated subsets, which has so far prevented both the selective targeting of these immunosuppressive cells and their use as potential biomarkers. In this context, we propose the concept of IMCGL, “pro-tumoral immunosuppressive myeloid cells of the granulocytic lineage”, to more accurately reflect the contentious nature and origin of granulocytic cells in the breast tumor microenvironment. Future research prospects related to the role of this myeloid landscape in breast cancer are further considered.

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“…CXCR2 inhibition prevented neutrophil accumulation in the pancreatic tumors and led to a T cell-dependent suppression of tumor growth [ 94 ]. Mehmeti-Ajradini et al [ 95 ] observed that G-MDSCs isolated from metastatic breast cancer cell patients reduced endothelial expression of CX3CL1 (fractalkine) and prevented infiltration of myeloid immune cells into the tumor.…”

Section: Evidence For Neutrophil Involvement In Cancermentioning

confidence: 99%

“…The G-MDSCs share many traits with immature LDNs that have been released from the bone-marrow before reaching full maturity [ 161 ]. However, not all LDNs are G-MDSCs [ 158 ], and G-MDSCs found in cancer may display heterogeneous morphology, including blast-like myelocytes, banded neutrophils as well as mature neutrophils [ 95 ]. G-MDSCs also share many pro-tumor features of tumor-associated neutrophils (TANs) [ 40 ].…”

Section: Neutrophil Heterogeneity and Subpopulations In Cancermentioning

confidence: 99%

Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

Sionov

2021

Cells

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Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.

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Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer

Cited by 16 publications

References 60 publications

Neutrophils in cancer carcinogenesis and metastasis

Neutrophils in cancer carcinogenesis and metastasis

Beyond Immunosuppression: The Multifaceted Functions of Tumor-Promoting Myeloid Cells in Breast Cancers

Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

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