Preface

Bone marrow-derived suppressor cells（MDSCs）It is a pathological activated neutrophil and monocyte with strong immunosuppressive activity. They are related to the regulation of immune responses under many pathological conditions and are closely associated with adverse clinical outcomes of cancer. There are important differences between MDSCs and typical neutrophils and monocytes, and the latest research describes some new genomic and metabolic features of MDSCs that shape their specific functions and contribute to targeted therapies based on these cells, particularly in cancer and autoimmune diseases. The function of MDSCs in the former exacerbates the disease, while MDSCs in the latter can limit the severity of the disease.

Definition and Basic Characteristics of MDSCs

There are two major types of MDSCs in humans and mice, classified according to their sources from granulocyte and monocyte lines, namely granulocyte/polymorphonuclear cell MDSCs（PMN-MDSCs）And monocytic MDSCs（M-MDSCs）. In addition, a small group of myeloid precursor cells with characteristics of bone marrow mesenchymal stem cells have been discovered in humans and named "early bone marrow mesenchymal stem cells". This group of cells has strong immunosuppressive function and is mainly composed of myeloid progenitor cells and precursor cells, accounting for less than 5% of the total number of MDSCs.

The pathological state of immune activation is a common feature of MDSCs, and typical bone marrow cell activation is a response to pathogens and tissue damage, mainly through danger related molecular patterns（DAMPs）Molecular patterns related to pathogens（PAMPs）And Toll like receptors（TLR）Activate to drive. In contrast, pathological activation is caused by the sustained stimulation of myeloid cells due to the long-term presence of myeloid growth factors and inflammatory signals in the environment of cancer, chronic infections or inflammation, and autoimmune diseases. Examples of such activation signals include cytokines and various growth factors, such as GM-CSF, M-CSF, IL-6, IL-1 β, adenosine signaling, or endoplasmic reticulum（ER）Stress signals.

In recent years, lectin type oxidized low-density lipoprotein receptor 1（LOX1）It has become a specific marker for human PMN MDSCs, which can be used to identify these cells in the blood of cancer patients and tumors. In addition, by detecting the expression of MHC II, M-MDSCs can be distinguished from peripheral blood monocytes, and recently discovered new molecules may help further describe these cell populations.

The main characteristic of MDSCs is their ability to suppress immune responses, including T cells, B cells, and natural killer cells（NK）Cellular mediated immune response. M-MDSCs and PMN MDSCs have key biochemical properties that suppress immune responses, including signal transduction and transcriptional activation factors 3（STAT3）Upregulation of expression, endoplasmic reticulum stress induction, arginase 1 expression, and S100A8/A9 expression.

They also haveFeatures may affect their ability to regulate different aspects of immune response. For example, PMN MDSCs prioritize the use of reactive oxygen species（ROS）Peroxynitrite, Arginase 1, and Prostaglandin E2（PGE2）M-MDSCs use nitric oxide to mediate immune suppression（NO）Immunosuppressive cytokines（Such as IL-10 and TGF - β）And immune regulatory molecules（Like PD-L1）The expression.

The transcriptional profile characteristics of tumor MDSCs

PMN-MDSCs have different transcriptional profile characteristics compared to neutrophils.Specifically, PMN MDSCs exhibit high expression of genes related to cell cycle, autophagy, G protein signaling, and CREB pathway.Neutrophils exhibit high expression of genes related to NF - κ B signaling through CD40, IL-1, IL-6, TLR, and TNF pathways, as well as lymphotoxin - β receptor signaling.

M-MDSCs and monocytes also have different transcriptional profile characteristics. M-MDSCs showed upregulation of several genes related to neutrophil function, including CXC chemokine receptor 1（CXCR1）. There is a significant overlap between the genetic characteristics of PMN MDSCs and M-MDSCs, indicating that both neutrophils and monocytes can acquire similar immunosuppressive features.

CD84 has been identified as a biomarker for MDSCs in tumors. CD84 is highly expressed in PMN MDSCs isolated from primary tumors and spleens, and MDSCs with high CD84 expression exhibit T cell inhibitory ability and increased reactive oxygen species production. In summary, MDSCs haveThe transcriptional profile is characterized by the expression of pro-inflammatory and immunosuppressive pathways. Distinguishing MDSCs from traditional monocytes and neutrophils is crucial for designing effective therapies targeting MDSCs.

Metabolic characteristics of tumor MDSCs

Metabolic reprogramming is one of the markers of tumors.Tumor cells reprogram their metabolism to maintain high energy demands, thereby supporting rapid proliferation, survival, and differentiation.The competition for nutrients and oxygen in the tumor microenvironment forces immune cells to adapt to their metabolism.MDSCs are selected throughofThe metabolic pathway perceives the environment and responds to maintain its inhibitory and pro tumor functions.

Lipid metabolism of MDSCs

There is currently ample evidence to suggest that lipid metabolism of MDSCs undergoes changes, which play a critical role in their differentiation and function.

Upregulation of scavenger receptor CD36 mediated lipid uptake facilitates the transition from glycolysis to fatty acid oxidation（FAO）As the main source of energy for tumor associated MDSCs. CD36 deficiency or FAO inhibition affects the inhibitory function of MDSCs, delays tumor growth, and improves the efficacy of chemotherapy and immunotherapy.

In recent years, fatty acid transporter 2（FATP2）Considered as a regulatory factor for the inhibitory function of PMN MDSCs. FATP2 is responsible for the uptake of arachidonic acid and subsequent synthesis of PGE2. The inhibition of FATP2 eliminated the inhibitory function of PMN MDSCs and improved the efficacy of tumor immunotherapy.

Glucose metabolism of MDSCs

MDSCs exhibit an increase in glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle during differentiation and activation. The upregulation of the glycolysis pathway prevents ROS mediated apoptosis by the antioxidant activity of the glycolytic intermediate phosphoenolpyruvate, thereby protecting MDSCs from apoptosis and promoting their survival.

Under hypoxic conditions, hypoxia inducible factor 1 α（HIF1α）The activation of MDSC induces a transition from oxidative phosphorylation to glycolysis. HIF1 α is a key regulatory factor for the differentiation and function of MDSCs in the tumor microenvironment. HIF1 α promotes the differentiation of M-MDSCs into tumor associated macrophages through a mechanism involving downregulation of CD45 tyrosine phosphatase activity and STAT3 activity.

Amino acid metabolism of MDSCs

MDSCs regulate T cell function by removing essential metabolites such as arginine, tryptophan, and cysteine from the microenvironment. One of the T cell inhibition mechanisms of MDSCs is the upregulation of arginase 1, which leads to a decrease in arginine levels. The breakdown metabolism of arginine through NOS2 is another key inhibitory mechanism of MDSCs, and the release of peroxynitrite can induce T cell apoptosis and inhibit T cell function and migration. IDO dependent tryptophan metabolism is another pathway through which MDSCs suppress immune responses. MDSCs induce IDO to reduce the level of tryptophan in the external environment, which decomposes this essential amino acid into N-formylkynurenine.

Targeted therapy application of MDSCs in tumors

Although bone marrow mesenchymal stem cells have a short lifespan in tissues, they are constantly recruited to chronic inflammatory sites, allowing them to produce long-lasting effects in these areas.However, due to their short lifespan in tissues, the pathological activation state of these cells in tissues is difficult to reverse.Therefore, effective treatment can be achieved by blocking the differentiation of MDSCs, inhibiting their migration to affected tissues, or by controlling the tissue microenvironment for targeted therapy.

Impact the fundraising of MDSCs

The migration of neutrophils and PMN MDSCs to tumors is mainly driven by the chemokine receptor CXCR2. Knocking out CXCR2 or blocking PMN-MDSC recruitment to tumors with small molecule CXCR2 inhibitors can improve the prognosis of metastatic sarcoma and enhance the efficacy of anti-PD-1 therapy in established tumors.

Clear MDSCs

MDSCs are short-lived cells that are constantly replaced and released into the bloodstream. The depletion of high renewal rate cells may be a challenge, but there are several methods that provide encouraging results. Chemotherapy drugs such as 5-fluorouracil, carboplatin, paclitaxel, or gemcitabine can reduce the number of circulating MDSCs and promote stronger anti-tumor immune responses, but these drugs are not specific to MDSCs and affect all rapidly proliferating cells, including anti-tumor T cells.

A more sophisticated approach is to use antibodies to recognize CD33, a marker expressed on the surface of human myeloid cells. In phase II clinical trials, compared to toxins（ozogamicin）Conjugated monoclonal antibodiesAnti-CD33 antibody（gemtuzumab）Showing a good effect in removing MDSCs expressing CD33.

The recognition of CD33 has been used for CD16 and IL-15 tri specific killer receptors in hematological malignancies（TriKE）. This molecule（GTB-3550）Cross linked expression of CD33 and CD16 by NK cells induces cytotoxicity and proliferation of ADCC and NK cells. althoughGTB-3550It has been proven to reduce the inhibitory effect of MDSCs on TIGIT mediated NK cells, but the absence of MDSCs dependent on ADCC may be another possible mechanism of action.

The activation of endoplasmic reticulum stress is a characteristic of MDSCs, which distinguishes them from monocytes and neutrophils. Activation of endoplasmic reticulum stress pathway induces DR5 on MDSC（A TRAIL receptor）Upregulation of this molecule can rapidly induce MDSC apoptosis by targeting it. An excitatory DR5 antibodyDS-8273aIt was also tested in a phase one clinical trial. This treatment has good tolerability and induces selective reduction of MDSCs in different types of advanced cancer patients, which is associated with an increase in progression free survival.

Liver X receptor（LXR）It has a significant impact on the survival of MDSC. LXR activation can induce apoptosis of MDSCs in tumor bearing mice through apolipoprotein E (APOE) signaling transduction, thereby significantly reducing the number of MDSCs. Preclinical tumor models respond well to two LXR agonists:GW3956 and RGX-104RGX-104 is currently undergoing a phase one clinical trial, and preliminary results show that the drug can promote T cell activation and effectively reduce the number of PMN-MDSC and M-MDSC in circulation.

Reprogramming of MDSCs

Blocking the immunosuppressive function of MDSC can enhance the anti-tumor immune response. Early research has shown that,All trans retinoic acid（ATRA）Promote the differentiation of mouse and human MDSCs into macrophages and dendritic cells, and kill PMN MDSCs. In the preclinical model of breast cancer, the removal of MDSCs through ATRA treatment has been proved to improve the efficacy of VEGFR2 inhibitors as anti angiogenesis therapy.

Using FATP2 inhibitorlipophermaTreating mice can significantly reduce tumor growth. In addition, it has a synergistic effect with anti-CTLA4 antibody therapy. As PGE2 biosynthesis is considered a downstream target of FATP2, these results are consistent with the role of PGE2 as an effective inhibitor of T cell function in cancer.

Recent studies have shown that the PERK pathway targeting endoplasmic reticulum stress response can reprogram tumor associated M-MDSCs into cells with anti-tumor functions. In preclinical models, inhibition of PERK enhances the efficacy of checkpoint inhibitors. Another approach is to target TOLLIP, a signaling adapter molecule expressed in bone marrow cells that participates in the immune suppression function of PMN MDSCs. Although TOLLIP inhibitors have not yet been tested in research, these findings make TOLLIP an interesting target for cancer immunotherapy.

Targeted therapy application of MDSCs in autoimmune diseases

In early studies, MDSCs showed protective effects against asthma and airway inflammation by inhibiting the TH2 type immune response, which is one of the main causes of airway inflammation. Adoptive transfer of MDSCs to mice with allergic airway inflammation can reduce the severity of the disease. In addition, MDSCs have also shown protective effects in mouse models of Sjogren's syndrome and arthritis.

MDSCs are also associated with the occurrence or progression of inflammatory bowel disease. In a mouse model of colitis, the use of histone methyltransferase inhibitors reduces the severity of the disease by inducing the accumulation of immunosuppressive MDSCs in the colon. In addition, mTOR inhibitors and clarithromycin acetate（A compound approved for the treatment of multiple sclerosis）Enhancing the inhibitory function of MDSCs has shown therapeutic efficacy in treating mouse colitis models.

prospect

New certificateIt has been shown that MDSCs play a crucial role in the formation of immune responses in many pathological environments.Although we have understood the key gene transcriptome and metabolic characteristics of these cells, the precise genomic features for identifying and analyzing MDSCs in clinical settings still need to be established.A major challenge will be to determine whether PMN MDSCs can be subdivided into smaller populations with specific functional characteristics, or whether they represent discrete single populations distinct from classical neutrophils;The same applies to M-MDSCs.

Finally,The challenge remains how to best selectively target MDSCs. Perhaps in the coming years, through strong efforts, we may see whether targeting these cells can improve clinical outcomes in different disease environments.

References:

1.

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021 Feb 1; 1-14.