Introduction
Main phenotypic and functional characteristics of MDSCs
Refs. | Phenotype (MDSCs) | Tumor tissue (TT)/ peripheral blood (PB) | NSCLC/SCLC | No. of patients | Implications |
---|---|---|---|---|---|
[14] | CD11b+CD14−CD15+CD33+ | PB | Advanced NSCLC | 41 | Decreased in the advanced-stage patients who had clinical benefit (PR or SD) and in the early-stage patients after removal of tumor. |
[15] | CD11b+CD14+S100A9+ | PB | Advanced NSCLC | 24 | Poor chemotherapy response and short PFS |
[16] | CD16lowCD11b+CD14−HLA-DR−CD15+CD33+ | PB | Advanced NSCLC | 185 | Significantly increased compared to healthy controls |
[17] | CD14+HLA-DR−/low | PB | NSCLC | 60 | Negatively correlated with PFS |
[18] | CD14+HLA-DR−/low | PB | SCLC | 42 | Independent biomarker for poor prognosis |
[19] | B7-H3+CD14+HLA-DR−/low | PB | NSCLC | 111 | Decreased RFS |
[20] | CD11b+CD14−HLA-DR−CD33+CD15+ ILT3high | PB | Stage IV NSCLC | 105 | Decreased OS |
[21] | lin−CD14−CD11b+ CD39+/CD73+PMN-MDSCs lin−CD14+CD11b+ CD39+/CD73+M-MDSCs | PB | NSCLC | 24 | Decreased with chemotherapy cycles in SD and PR groups, increased in PD group. |
[22] | Lin−CD14 + CD15 + CD11b + CD33 + HLA-DR− | PB | NSCLC | 110 | Independent prognostic marker for decreased PFS and OS. |
[23] | Lin−CD14−HLA-DR− | PB | NSCLC | 46 | After three cycles, bevacizumab-based chemotherapy significantly reduced the level of Lin−CD14−HLA-DR− cells. |
[24] | Lox-1+ PMN-MDSCs | PB | NSCLC | 34 | Patients with a higher ratio of Tregs to Lox-1+PMN-MDSCs in the blood after the 1st nivolumab had better PFS. |
[25] | Lin−CD33 + CD14 + CD15− HLA-DR− | PB | Metastatic NSCLC | 61 | Decreased OS in anti-PD-1 treatment. |
[26] | SSClowLin−HLA-DR−/LOWCD33+ CD13+CD11b+CD15+CD14− | PB | stage IIIB or IV NSCLC | 53 | PMN-MDSCs (≥6 cell/μl) showed a significantly improved survival in anti-PD-1 treatment. |
[27] | CD33+CD11b+CD14− PMN-MDSCs CD33+CD11b+CD14+HLA-DR−/low M-MDSCs | PB | NSCLC | 7 | Both subtypes decreased after SBRT treatment. |
[28] | CD11b+HLA-DR−/lowCD14−CD15+ PMN-MDSCs CCR5+HLA-DR−/lowCD11b+CD14+CD15− M-MDSCs | TT and PB | Resectable NSCLC | 42 | TT PMN-MDSCs displayed higher PD-L1 expression levels than the same cells in the PB. Significant correlations between lower total PMN-MDSCs and CCR5+ M-MDSCs frequencies in the peripheral blood and improved RFS. |
Mechanisms underlying MDSC-mediated immunosuppression in LC
Metabolic mechanisms
STAT signaling pathway
Exosomes
Caspase recruitment domain-containing protein 9
Long noncoding RNAs
MicroRNA
Tissue factor
Endoplasmic reticulum stress
Significance of MDSCs in LC
Role of MDSCs in the development of LC
MDSCs are associated with chemotherapy resistance
The effect of radiotherapy on MDSCs
MDSCs are associated with the efficacy of immune checkpoint inhibitor treatment
MDSCs in murine models of LC
Therapeutic MDSC-targeted strategies for inhibiting LC
Refs. | Therapeutic strategy/compound | Targeted process | Tumor model | Implications |
---|---|---|---|---|
[98] | P53 vaccine and ATRA | Lin−HLA-DR−CD33+MDSCs depletion | Extensive stage SCLC patients | 1. Enhancement p53-specific immune response 2. Better clinical response |
[99] | Bevacizumab and EGFR TKI | Reduced the level of circulating S100A9 positive M-MDSCs | Patients with IV lung adenocarcinoma harboring an activating EGFR mutation | 1. Improvement intracranial control rate and intracranial lesion TTP in patients with EGFR-mutant lung adenocarcinoma 2. Increased gene signatures associated with CD8 effector genes, Th1 chemokines, and NK cells. |
[100] | Cabergoline | Reduced the accumulation of MDSCs | LLC1 murine model | 1. Reduction angiogenesis 2. Inhibition lung cancer growth |
[101] | Cimetidine | Reduced the accumulation of MDSCs | 3LL murine model | 1. Inhibition of tumor growth 2. Enhancement MDSCs apoptosis |
[9] | Monoclonal anti-Gr1 or anti-Ly6G Abs | MDSC depletion | 3LL murine model | 1. Increased NK- and CD8+ T cell activity 2.Increased anti-angiogenic but reduced pro-angiog marker expression 3.Reduced 3LL lung metastases 4.Inhibition of tumor growth |
[9] | BMA-OVA + anti-Gr1 Abs | MDSC depletion | 3LL-OVA murine model | 1. Tumor growth inhibition 2. Increased: splenic production of IFNγ and frequency of IFNγ producing CD4 and CD8 memory (CD44) and activation (CD69) marker expressing T cells |
[102] | Gemcitabine + SOD mim | MDSC depletion | 3LL murine model | 1. Inhibition tumor growth 2. Enhances the quantity and quality of both effector and memory CD8+T cell responses. 3. Enhanced cytolytic CD8+ T cell response and further decreased Treg cell infiltration. 4. Improved long-term survival of mice bearing lung cancer 5. Thiol-dependent STAT-3 activation is enhanced in memory cells |
[103] | IDO1 inhibitor | Reduced the percentages of F4/80+Gr1intCD11b+ MDSCs | Anti-PD-1-resistant cell line (344SQ-R) murine model | 1. Inhibition suppresses tumor growth and lung metastases in anti-PD1 resistant tumors 2. Reduction both Kyn levels and Kyn:Trp 3. Reactivation CD8+ T cells 4. Reduction IDO1 expression of F4/80 + Gr1intCD11b + MDSCs and the percentage of IDO1+CD11b+ DCs in anti-PD1 resistant tumors. |
[104] | Entinostat+ anti-PD-1 antibody | Reduced the immunosuppressive activity of MDSCs | 3LL murine model | 1. Enhanced anti-PD-1 immunotherapy 2. Decrease in the protein levels of FoxP3 in the circulating CD4+FoxP3+cell subtype 3. Increase in the CD8+ T - Treg cells ratio 4. Reduction of tumor infiltrating macrophages 5. Increase in MDSC associated trafficking/accumulation cytokines, anti-tumor chemokines, and cytokines |
[105] | CCL2 antagonist+ anti-PD-1 antibody | Decreased MDSC recruitment | 3LL murine model | 1. Increased the survival time of tumor-bearing mice 2. Enhanced CD4+ and CD8+ T cell infiltration and activation |
[106] | MEK Inhibitor (Trametinib) + either anti-PD-1 or anti-PD-L1 mAbs | Attenuation of Ly6Ghigh PMN-MDSCs | p53floxflox;KrasLSL-G12D/+.R0sa26LSL-Luciferase/LSL-Luciferase (PKL) - transgenic lung cancer mouse model | 1. Increased antitumor response and survival outcome 2. Increased of tumor-infiltrating CD8+ and CD4+ T cell 3. Suppressed tumor cell proliferation and lead to apoptosis of tumor cells |
[107] | Carnosic acid | Decreased function and accumulation of MDSCs | 3LL murine model | 1. Enhanced the anti-growth effects of cisplatin on LLC xenografts and reduced the side effects of cisplatin. 2. Increased antitumor response 3. Enhanced cisplatin-induced tumor proliferation inhibition and apoptosis 4. Promoted CD8+ T cells-mediated antitumor immune response |
[108] | Resveratrol | Decreased PMN-MDSC accumulation | 3LL murine model | 1. Increased antitumor response and survival outcome 2. Promoted the apoptosis of PMN-MDSCs, impair PMN-MDSCs immunosuppressive capacity 3. Boosted M-MDSCs maturation and differentiation |
[109] | Curcumin | Decreased MDSC accumulation | 3LL murine model | 1. Increased antitumor response 2. Promoted the maturation and differentiation of MDSCs 3. Inhibited the expression level of Arg-1 and ROS 4. Decreased the level of IL-6 |