MDSCs and Their Roles in Premetastatic Niche Formation
MDSCs Persist in Distant Organs After Primary Tumor Resection
Disease | Surgery | MDSCs subtype | Biological function of MDSCs | Reference |
---|---|---|---|---|
Lung cancer | Thoracotomy | CD11b+CD33+HLA-DR– MDSCs | More efficient in promoting angiogenesis and tumor growth than MDSCs isolated before surgical operation | |
Lung cancer | Thoracotomy | CD11b+CD33+HLA-DR–CD14+MDSCs | Surgery-induced M-MDSCs were more efficient in suppressing T-cell proliferation, more potent in expending Treg when cocultured with autologous T cells in vitro | |
Bladder cancer | Radical cystectomy | Lin− CD11b+ CD33+ MDSCs | Every unit increase in MDSC count from surgery to 2 day postoperatively, the odds of infection rate 90 day after surgery increased by 2.5% | |
Gastric cancer | Resection surgery | CD14+ HLA-DR− CD11b+ CD33+ MDSCs | Produced IDO and arginase and suppressed T cell functions | |
Prostate cancer | Radical prostatectomy | CD14−HLA-DR−CD33+CD11b+ MDSCs | – | |
Breast Cancer | Radical or partial mastectomy | CD33+HLA-DR− CD15+CD11b+ MDSCs | Increased levels of MDSC levels were associated with decreases in the number of NK cells | |
Esophageal cancer | Radical resection | G-MDSC | A high level of G-MDSCs can be used to determine the incidence of sepsis in preoperative esophageal cancer patients | |
Non-cancer disease | Hip arthroplasty | CD11b+CD14+CD33+HLA-DRlow MDSCs | Surgery evoked a coordinated functional response that was restricted to 6 major intracellular signaling molecules (STAT1, STAT 3, STAT 5, p38, S6, CREB) | |
Cardiopulmonary Bypass | CD15+CD11b+CD14−HLA-DR−MDSCs | MDSCs expansion was related to the impairment of T cell proliferation, cytotoxicity, and IFN-γ secretion |
Mechanisms of MDSCs Infiltration After Primary Tumor Resection
Surgical Stress Promotes MDSCs Expansion
Surgical Trauma Releases DAMPs to Activate, Expand, and Recruit MDSCs
Surgery-Induced Cytokines Enhance MDSC Mobilization and Function
Cytokines | Name | Biological function in MDSCs | Biological function in surgery |
---|---|---|---|
Interleukins | IL-6 | ||
IL-8 | Attracts MDSCs and elicits extrusion of neutrophil extracellular traps56 | Proinflammatory cytokine responds to surgical stress57 | |
Colony-stimulating factors (CSF) | GM-CSF | Recruit and expand MDSCs, promote migration and differentiation of MDSCs58 | GM-CSF ameliorates microvascular barrier integrity via pericyte-derived Ang-1 during wound healing59 |
G-CSF | Mobilize G-MDSCs to the lung pre-metastatic niche60 | Angiogenic circulating factor responding to surgery61 | |
Chemokines | CXCL1 | Recruits CXCR2-positive MDSCs to form a premetastatic niche, promoting liver metastases62 | Proangiogenic chemokine, that participate wound healing |
CCL2 | CCL2/CCR2 axis is important for MDSC recruitment63 | Evaluation of CCL2 help guide postsurgical management for clear-cell renal cell carcinoma patients64 | |
SDF-1/CXCL 12 | SDF-1/CXCR4-mediated recruitment of MDSCs from bone marrow65 | Chemokine, involving wound healing66 | |
Growth factors | VEGF | Activate NF-κB signals, producing CXCL1 to recruit CXCR2+ MDSC62 | One of the most potent proangiogenic factors during wounds healing67 |
Interferon | IFN-γ | IFN-γ significantly upregulated iNOS expression in M-MDSCs68 | Mediating postoperative proinflammatory responses69 |
Tumor necrosis factor (TNF) | TNF-α | Cytokine attracting neutrophils and monocytes to pre-metastatic niche; Signaling of TNF-R2 promoted MDSC survival through upregulation of c-FLIP and inhibition of caspase-8 activity70 | First cytokine responding to injury, trigger an inflammatory cascade. Endogenous wound TNF-α down-regulates collagen synthesis during normal wound healing71 |
Transforming growth factor (TGF) | TGF-β | Factor secreted by MDSCs, that with strong immunosuppressive function166 | TGF-β exhibits two postoperative peaks of secretion at 2 h and 3–4 days. Stimulates angiogenesis and fibroblast proliferation72 |
Extracellular matrix | MMP9 | MMP-9-cleaved OPN fragment, OPN-32 kDa, was responsible for MDSCs expansion73 | Serum MMP-9 increased significantly 4 days after surgery and was still high 30 days after surgery; play a role in normal tissue remodeling events74 |
LOX | Promote the ECM remodeling to recruit MDSC75 | A key enzyme required for crosslinking and deposition of insoluble collagen, and targeting LOX might be an approach to reduce adhesions76 | |
Fibronectin | Fibronectin is a large glycoprotein capable of interacting with various ECM molecules produced by a variety of cell types and involved in cell attachment and chemotaxis79 | ECM derived DAMPs after surgery that activate inflammation and monocyte activation; also participated in wound healing80 | |
DAMPs | S100A8/9 | Causing neutrophil migration to inflammatory sites; a biomarker of postoperative organ injury85 | |
Prostaglandin-endoperoxide synthase | COX-2 | Catalyzed the synthesis of PGE-2, which exacerbated the immunosuppressive activity of MDSC81 | An enzyme responsible for the production of PGs that respond to surgical stress82 |
Surgery Promotes Extracellular Matrix Remodeling
Surgery Enhances MDSC Infiltration by Promoting Vascular Permeability
Therapies Targeting MDSCs for Premetastatic Niche Disruption After Surgery
Strategies | Drugs | Clinical trial | Mechanisms | Reference |
---|---|---|---|---|
Anti-surgical stress | β-blockade (Propranolol) | NCT03152786/NCT02013492 | Block the β2-AR signal in MDSCs | |
COX-2 inhibitor (Celecoxib, Etodolac) | NCT03896113/NCT03864575/NCT03838029 | Disruption of the COX-2/PGE-2 signals; reducing MDSC recruitment and differentiation, repressing MDSC-associated suppressive factors such as Arg-1 and ROS production | ||
Anti-DAMPs | Anti-HMGB 1 antibody | Preclinical | Ameliorated the trauma-induced attenuated T-cell responses and accumulation of MDSCs in the spleens seen 2 days after injury | |
S100A8/A9 neutralizing antibody | Preclinical | Neutralizing extracellular S100A8/A9 | ||
Anti-inflammatory signals | NF-κB inhibitor (BAY11-7082) | Preclinical | Inhibiting NF-κB mediated CXCL1, CXCL2 and CXCL5 production, that reduce the chemotaxis of MDSCs; Inhibition NLRP3 inflammasome activation and the increased pyroptosis | |
NLRP3 inhibitor (MCC950/CY-09/OLT1177/Tranilast/Oridonin) | Preclinical | Inhibition NLRP3 inflammasome activation and the following IL-1β secretion | ||
IL-1β (Anakinra) | NCT02780583/NCT04359784 | Inhibit the IL-1β inducing CCL5, CXCL12, CCL2, and CXCL5 expression | ||
Epigenetic drugs | HDAC (Entinostat) | NCT01207726/NCT03501381/NCT03552380 | Downregulating CCR2 and CXCR2 expression; promoting MDSC differentiation into a more-interstitial macrophage-like phenotype | |
DMNT (5-azacytidine) | NCT01207726/NCT03709550 | |||
Depletion of MDSCs | Chemotherapy (Gemcitabine/5-FU) | NCT04331626/NCT01803152/NCT02090101 | Depletes G-MDSCs, M-MDSCs, macrophages, and eosinophils | |
TKI(Pazopanib/Bevacizumab) | NCT01832259/NCT01218048 | Blockade of VEGF and c-KIT signaling; inhibit STAT3 | ||
Differentiating MDSCs | ARTA | NCT02403778 | Inhibits retinoic signaling to shift the differentiation of MDSC into mature myeloid cells, such as macrophages and dendritic cells | |
Blocking MDSCs trafficking | CXCR2 inhibitor (AZD5069, Reparixin, SX-682) | NCT03161431/NCT02499328/NCT02370238 | Inhibit CXCR2 mediated MDSCs trafficking | |
CCR2 inhibitor (BMS-813160, RS504393) | NCT04123379/NCT03767582/NCT03496662 | Improved the prognosis by blocking chemotaxis of M-MDSCs | ||
Inhibit MDSCs activity | Stat3 inhibitor (AZD9150) | NCT02499328 | A marked decrease in G-MDSC within the peripheral blood mononuclear cells | |
NF-κB inhibitor (BAY11-7082) | Pre-clinical | Inhibit the activated NF-kB signal induced by DAMPs-PRR interaction | ||
Targeting the ECM remodeling | LOX inhibitor (β-aminopropionitrile) | Pre-clinical | Reduce the surgery induced hypoxia related LOX, and ECM remodeling | |
Repair vascular leakage | IL-6 inhibitor (Tocilizumab) | NCT04370834) | Inhibit IL-6 mediated inflammatory response the repair the vascular leakage | |
C5 antibody (Ravulizumab) | NCT04369469 | Inhibit the C5a-C5R signal on vascular endothelial cells | ||
Restore the immunity after surgery | TGF-β inhibitor (LY3200882/LY2157299/EW-7197) | NCT04031872/NCT03143985/NCT02452008 | Reverse the MDSC secreted TGF-β mediated immunosuppression | |
PDE5 inhibitor (Sildenafil, Tadalafil) | NCT02544880 | Targeting MDSC expression and function of Arg-1 and iNOS | ||
ERAS | NCT02644603 | Pre-rehabilitation, nutrition, pain management to rapid restore immunity after surgery |