Background
The immunosuppressive cells in TME
Myeloid-derived suppressive cells (MDSCs)
Tumor-associated macrophages (TAMs)
Cell type | Sub-type | Phenotypes | Functions |
---|---|---|---|
M-MDSCs | Mouse: CD11b+Ly6ChighLy6G− Human: CD11b+CD14+CD33+HLA-DR−CD15− CD11b+CD14+CD33+HLA-DR−CD15+ | Induce Non-specific suppression; Produce cytokines that support tumor angiogenesis; Induce anti-tumor therapy resistance | |
PMN-MDSCs | Mouse: CD11b+Ly6G+Ly6Clow Human: CD11b+CD14−CD15+CD33+HLA-DR− CD11b+CD14−CD66b+ | Induce antigen-specific T cell tolerance and non-specific suppression; Produce cytokines that support tumor angiogenesis | |
eMDSCs | Human: CD11b+CD14−CD15−CD33+HLA-DR− | Exist as free cells in the peripheral blood and as enriched cell populations in the tumor microenvironment | |
Macrophages [28] | M1 | Mouse: CD11b+F4/80+CD206− Human: CD64+CD80+ | Produce immune killing molecules; Secrete specific inflammatory cytokines; Display pro-inflammatory features |
M2 | Mouse: CD11b+F4/80+CD206+ Human: CD163+CD86+ | Remodel the ECM; Brake down the basement membrane; Promote angiogenesis; Construct immunosuppression; Recruit Tregs and MDSCs; Orchestrate tumor development and distant metastasis | |
N1 | Mouse: CD11b+Ly6G+CD54+CD16+CD170low, CD177+ (in CRC) Human: CD11b+CD66b+CD101+CD54+HLA-DR+CD86+CD15highCD170low, CD177+ (in CRC) | Associate with anti-tumor properties; Characterized by a normal density, a hypersegmented nucleus and a cytotoxic activity toward cancer cells | |
N2 | Mouse: CD11b+Ly6G+PDL1+CD170high Human: CD11b+CD66b+PDL1+CD170high | Associated with pro-tumor properties; Have immunosuppressive activity | |
NI | Mouse: CD11b+Ly6G+CD117+CD170lowCD101−CD84+JAML+ Human: CD11b+CD66b+CD117+CD10−CD16int/lowLOX1+CD84+JAML+ | Immature neutrophils endow with immunosuppressive properties appear in the circulation, primary tumors and metastases | |
NISG | Mouse: CD11b+Ly6G+, IFIT1, IRF7, RSAD2 Human:
CD11b+CD66b+, IFIT1, IRF7, RSAD2 | Neutrophils with interferon-stimulated gene signatures | |
Plasmacytoid DCs | Mouse: B220+CD11clowMHC-II+CD303+ Human: B220+CD11clowMHC-II+CD317+ | Contribute to tumor-induced immunosuppression | |
Conventional DCs | Mouse: Lin−ZBTB46+MHC-II+CD141+; Lin−ZBTB46+MHC-II+CD11c+; CD11b+ | Induce Th2 responses; Suppress CD8+ T cell function | |
Inflammatory DCs | Mouse: CD11c+MHC-II+CD11b+F4/80+Ly6C+CD206+CD115+CD107b+FcɛRI+CD64+ Human: CD11c+CD115+CD1c+CD1a+FcɛRI+CD206+CD172a+CD14+CD11b+ | Produce high levels of pro-inflammatory cytokines, such as TNF, IL-6, and IL-12 | |
nTregs | CD4+CD25+Foxp3+CD127lo/− | Maintain normal immune tolerance and control the inflammatory response | |
iTregs | CD4+CD25+Foxp3+CD127lo/− | Inhibit the anti-tumor immune action of effector T cells, NK cells and DCs; Secrete inhibitory cytokines; Kill effector cells by granzymes and perforin; Produce factors to facilitate Tregs expansion and reinforce the suppressive environment | |
B10 cells | Mouse: CD5+CD1dhi Human: CD19+CD24hiCD27+ | Produce IL-10, and suppress effector CD4+ T cells, monocytes, and DCs; Induce Tregs through TGF-β | |
T2-MZP cells | Mouse: CD19+CD21hi; CD23hiCD24hi Human: CD19+CD24+CD38+ | Produce IL-10, and suppress effector CD4+ T cells; Induce Tregs and decrease CD8+ T cells by TGF-β |
Tumor-associated neutrophils (TANs)
Regulatory T cells (Tregs)
Tumor-associated dendritic cells (tDCs)
Other immunosuppressive cells
Targeting immunosuppressive cells in cancers
MDSC-based therapies
Depleting the populations of MDSCs
Target | Agent | Tumor types and combinational therapies | Phase | Sample size | Clinical trial number |
---|---|---|---|---|---|
CXCR2 inhibitor | AZD5069 | Metastatic Castration Resistant Prostate Cancer + Enzalutamide | I/II | 86 | NCT03177187 |
SX-682 | Pancreatic Cancer + Nivolumab | I | 20 | NCT04477343 | |
Melanoma + Pembrolizumab | I | 77 | NCT03161431 | ||
CCR5 inhibitor | Vicriviroc | Advanced/Metastatic Microsatellite Stable Colorectal Cancer + Pembrolizumab | II | 42 | NCT03631407 |
Maraviroc | Advanced Metastatic Colorectal and Pancreatic Cancer + Nivolumab + Ipilimumab | I | 50 | NCT04721301 | |
CCR5 antibody | Leronlimab | Locally Advanced or Metastatic Solid Tumors | II | 30 | NCT04504942 |
STAT3 inhibitor | OPB-31121 | Advanced Cancers | I | 24 | NCT00955812 |
AZD9150 | Advanced Solid Tumors + Durvalumab | I | 76 | NCT03421353 | |
WP1066 | Recurrent Malignant Glioma and Brain Metastasis from Melanoma | I | 33 | NCT01904123 | |
TTI-101 | Advanced Cancers | I | 60 | NCT03195699 | |
SC-43 | Advanced NSCLC and Advanced Biliary Tract Cancer + Cisplatin | I/II | 100 | NCT04733521 | |
OPB-51602 | Advanced Cancer | I | 45 | NCT01423903 | |
JAK/STAT3 inhibitor | Ruxolitinib | Head and Neck Squamous Cell Carcinoma | II | 45 | NCT03153982 |
PDE5 inhibitor | Tadalafil | Head and Neck Squamous Cell Carcinoma | II | 40 | NCT01697800 |
Sildenafil | Solid Tumor + Regorafenib | I | 32 | NCT02466802 | |
COX2 inhibitor | Celecoxib | Lung Cancer + Radiation Therapy | I/II | 21 | NCT00046839 |
Colon Carcinoma + Nivolumab/Ipilimumab | II | 60 | NCT03026140 | ||
Breast Cancer | III | 2639 | NCT02429427 | ||
Cervix Neoplasms | I/II | 31 | NCT00152828 | ||
Endometrium Cancer | II | 48 | NCT03896113 | ||
HDAC inhibitor | Entinostat | Metastatic Colorectal Cancer + Azacitidine | II | 47 | NCT01105377 |
Vorinostat | Locally Advanced NSCLC + Chemotherapy and Radiation Therapy | I | 18 | NCT01059552 | |
Malignant Solid Tumor + Hydroxychloroquine | I | 72 | NCT01023737 | ||
Quisinostat | NSCLC/Epithelial Ovarian Cancer + Chemotherapy | I | 51 | NCT02728492 | |
SB939 | Prostate Cancer | II | 32 | NCT01075308 | |
Panobinostat | Melanoma + Ipilimumab | I | 17 | NCT02032810 | |
Chidamide | Cervical Cancer + Toripalimab | I/II | 40 | NCT04651127 | |
CHR-3996 | Solid Tumor | I | 40 | NCT00697879 | |
Vitamins | ATRA | Breast Cancer + Anastrozole | II | 112 | NCT04113863 |
Pancreatic Cancer + Chemotherapy | II | 170 | NCT04241276 | ||
Prostate Cancer + 5-Azacitidine + Lupron | II | 20 | NCT03572387 | ||
Melanoma + Pembrolizumab | I/II | 26 | NCT03200847 | ||
Casein kinase inhibitor | Silmitasertib (CX 4945) | Advanced Basal Cell Carcinoma | I | 26 | NCT03897036 |
Cholangiocarcinoma + Chemotherapy | I/II | 127 | NCT02128282 | ||
Chemotherapy | Low-Dose Capecitabine + Bevacizumab | Glioblastoma | I | 12 | NCT02669173 |
LXR Agonist | RGX-104 | Malignant Neoplasms + Immunotherapy/Chemotherapy | I | 135 | NCT02922764 |
Tyrosine kinase inhibitor | Pazopanib | Solid Tumors | II | 57 | NCT01956669 |
Solid Tumors + Topotecan | I/II | 66 | NCT02303028 | ||
Sarcoma + Durvalumab | II | 37 | NCT03798106 | ||
Ibrutinib | Malignant Solid Tumors + Nivolumab | I | 15 | NCT03525925 | |
Lung Cancer | I/II | 13 | NCT02321540 | ||
Gastroesophageal Cancer | II | 17 | NCT02884453 |
Blockade of MDSCs migration and recruitment
Inhibiting the activity of MDSCs
Promoting the differentiation and maturation of MDSCs
Inhibiting MDSCs metabolism
The TAMs-based targeted therapies
Depleting TAMs and blocking the recruitment of TAMs
Target | Agent | Tumor types and combinational therapies | Phase | Sample size | Clinical trial number |
---|---|---|---|---|---|
CSF1-R inhibitor | Pexidartinib (PLX3397) | Metastatic Breast Cancer + Eribulin | Ib/II | 67 | NCT01596751 |
Prostate Adenocarcinoma + Radiation Therapy + Antihormone Therapy | I | 8 | NCT02472275 | ||
Metastatic/Advanced Pancreatic or Colorectal Cancers + Durvalumab | I | 48 | NCT02777710 | ||
Pigmented Villonodular Synovitis/Tenosynovial Giant Cell Tumor | III | 120 | NCT02371369 | ||
DCC-3014 | Sarcoma + Avelumab | I | 48 | NCT04242238 | |
Advanced Tumors and Tenosynovial Giant Cell Tumor | I/II | 120 | NCT03069469 | ||
ARRY-382 | Advanced Solid Tumors + Pembrolizumab | II | 82 | NCT02880371 | |
Metastatic Cancer | I | 26 | NCT01316822 | ||
SNDX-6352 | Unresectable Intrahepatic Cholangiocarcinoma + Durvalumab | II | 30 | NCT04301778 | |
Solid Tumor + Durvalumab | I | 45 | NCT03238027 | ||
BLZ945 | Advanced Solid Tumors + PDR001 | I/II | 200 | NCT02829723 | |
CSF1-R antibody | Cabiralizumab (BMS-986227) | Peripheral T Cell Lymphoma + Nivolumab | II | 33 | NCT03927105 |
Advanced Solid Tumors + Nivolumab | I | 295 | NCT02526017 | ||
Solid Tumors + Nivolumab + APX005M | I | 120 | NCT03502330 | ||
Pigmented Villonodular Synovitis/Diffuse Type Tenosynovial Giant Cell Tumor | I/II | 75 | NCT02471716 | ||
IMC-CS4 (LY3022855) | Solid Tumor | I | 72 | NCT01346358 | |
Solid Tumor + Durvalumab/Tremelimumab | I | 178 | NCT02718911 | ||
Pancreatic Cancer + Cyclophosphamide + Pembrolizumab | I | 12 | NCT03153410 | ||
RO5509554/Emactuzumab/RG7155 | Advanced Solid Tumors | I | 217 | NCT01494688 | |
VEGFR/Aurora B/CSF1-R inhibitor | Chiauranib | Hepatocellular Carcinoma | I/II | 27 | NCT03245190 |
Small Cell Lung Cancer | I | 27 | NCT03216343 | ||
Ovarian Cancer | I/II | 25 | NCT03166891 | ||
VEGFR/KIT/RET/BRAF/CSF1-R inhibitor | Regorafenib | Hepatocellular Carcinoma + Nivolumab | I/II | 60 | NCT04170556 |
Hepatocellular Carcinoma | II | 171 | NCT04476329 | ||
VEGFR/FGFR/PDGFRβ/Kit/RET/TrkA/FLT3/CSF1-R inhibitor | Dovitinib (TKI258, Novartis) | Gastrointestinal Stromal Tumors | II | 30 | NCT01440959 |
MET/CSF1-R/SRC inhibitor | TPX-0022 | Advanced Solid Tumors with MET mutation | I | 120 | NCT03993873 |
AXL/MER/CSF1-R inhibitor | Q702 | Solid Tumor | I | 78 | NCT04648254 |
CCL2 antibody | CNTO888 | Solid Tumors + Gemcitabine/Docetaxel/Paclitaxel and Carboplatin | I | 53 | NCT01204996 |
CCR2 antibody | MLN1202 | Metastatic Cancer | II | 44 | NCT01015560 |
CCR2/5 inhibitor | BMS-813160 | NSCLC/HCC + Nivolumab | II | 50 | NCT04123379 |
Pancreatic Ductal Adenocarcinoma + Gemcitabine + Nab-paclitaxel + Nivolumab | I/II | 39 | NCT03496662 | ||
CXCR4 inhibitor | BL-8040 | Metastatic Pancreatic Adenocarcinoma + Pembrolizumab | II | 23 | NCT02907099 |
Plerixafor (Mozobil) | Advanced Pancreatic, Ovarian and Colorectal Adenocarcinomas | I | 26 | NCT02179970 | |
Metastatic Pancreatic Cancer + Cemiplimab | II | 21 | NCT04177810 | ||
Bisphosphonates | Zoledronic Acid | Hormone-Refractory Prostate Cancer | II | 30 | NCT00636740 |
Bone Metastatic NSCLC | II | 60 | NCT04325776 | ||
Ibandronic Acid | Breast Cancer | II | 171 | NCT02616744 | |
Alendronate Sodium | Breast Cancer | III | 303 | NCT00122356 | |
Trabectedin | Trabectedin | Liposarcoma/Leiomyosarcoma | II | 105 | NCT02247544 |
Soft Tissue Sarcoma + Olaratumab | I | 28 | NCT03985722 | ||
Ovarian and Uterine Carcinosarcoma | II | 45 | NCT02993705 | ||
Malignant Pleural Mesothelioma | II | 145 | NCT02194231 | ||
Metastatic Adult Soft Tissue Sarcoma + Nivolumab | II | 92 | NCT03590210 | ||
Pancreatic Cancer | II | 25 | NCT01339754 | ||
Advanced Soft Tissue Sarcomas | II | 132 | NCT00003939 | ||
TLR 4 agonist | GLA-SE | Adult Soft Tissue Sarcoma | I | 16 | NCT02180698 |
Merkel Cell Carcinoma | I | 10 | NCT02035657 | ||
GSK1795091 | Cancer | I | 42 | NCT02798978 | |
TLR 7/8 agonist | TransCon TLR7/8 Agonist | Solid Tumor + Pembrolizumab | I/II | 140 | NCT04799054 |
BDB018 | Solid Tumor + Pembrolizumab | I | 50 | NCT04840394 | |
NKTR-262 | Solid Tumor | I/II | 64 | NCT03435640 | |
TLR 7 agonist | RO7119929 | Hepatocellular Carcinoma, Biliary Tract Cancer, Solid Tumors With Hepatic Metastases | I | 100 | NCT04338685 |
Imiquimod | Breast Cancer | II | 10 | NCT00899574 | |
TLR 9 agonist | SD-101 | Pancreatic Adenocarcinoma + Nivolumab + Radiation Therapy | I | 6 | NCT04050085 |
Solid Tumor + BMS 986,178 | I | 12 | NCT03831295 | ||
CMP-001 | Melanoma + Pembrolizumab | II | 54 | NCT04708418 | |
Pancreatic Adenocarcinoma and Melanoma + INCAGN01949 | I/II | 42 | NCT04387071 | ||
IMO-2125 (Tilsotolimod) | Refractory Melanoma + Ipilimumab | III | 454 | NCT03445533 | |
Malignant Melanoma | II | 214 | NCT04126876 | ||
EMD 1,201,081 | Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck + Cetuximab | II | 107 | NCT01040832 | |
CD40 agonist antibody | Selicrelumab (RO7009789) | Solid Tumors + Atezolizumab | I | 140 | NCT02304393 |
RO7300490 | Solid Tumors + Atezolizumab | I | 280 | NCT04857138 | |
LVGN7409 | Cancer | I | 126 | NCT04635995 | |
CP-870,893 | Melanoma + Tremelimumab | I | 25 | NCT01103635 | |
Mitazalimab | Metastatic Pancreatic Ductal Adenocarcinoma + Chemotherapy | I/II | 70 | NCT04888312 | |
CDX-1140 | Breast Cancer + CDX-301, Radiotherapy, and Poly-ICLC | I | 36 | NCT04616248 | |
APX005M | Neoadjuvant Therapy for Rectal Cancer + Chemotherapy | II | 58 | NCT04130854 | |
Anti-CD47 antibody | ZL-1201 | Advanced Cancer | I | 66 | NCT04257617 |
IBI188 | Advanced Malignancies | I | 92 | NCT03717103 | |
Hu5F9-G4 | Solid Tumor | I | 88 | NCT02216409 | |
STI-6643 | Solid Tumor | I | 24 | NCT04900519 | |
AK117 | Neoplasms Malignant | I | 162 | NCT04728334 | |
ALX148 | Head and Neck Cancer + Pembrolizumab | II | 111 | NCT04675294 | |
AO-176 | Solid Tumor | I/II | 183 | NCT03834948 | |
Anti-CD47/PD-1 bispecific antibody | HX009 | Advanced Solid Tumor | II | 210 | NCT04886271 |
Advanced Solid Tumor | I | 21 | NCT04097769 | ||
PF-07257876 | Advanced or Metastatic Tumors | I | 90 | NCT04881045 | |
IBI322 | Advanced Solid Tumor | I | 36 | NCT04912466 | |
Advanced Solid Tumor | I | 45 | NCT04338659 | ||
Advanced Solid Tumor | I | 218 | NCT04328831 | ||
PI3Kγ inhibitor | IPI-549 | Head and Neck Squamous Cell Carcinoma | II | 15 | NCT03795610 |
Modified Vitamin D Binding Protein Macrophage Activator | EF-022 | Solid Tumors | I | 24 | NCT02052492 |
Migration Inhibitory Factor (MIF) | Anti-MIF Antibody | Malignant Solid Tumors | I | 68 | NCT01765790 |
Targeting the activation of TAMs
Modulating the phagocytosis of TAMs
Chimeric antigen receptor macrophage (CAR-M) cell therapy
TANs-related therapies
Depleting TANs and inhibiting their recruitment
Inhibiting the functions of TANs
Blocking the development of TANs
Reprogramming TANs
Tregs-related therapies
Depletion of Tregs
Target | Agent | Tumor types and combinational therapies | Phase | Sample size | Clinical trial number |
---|---|---|---|---|---|
Anti-CD25 antibody | Daclizumab | Melanoma | I/II | 15 | NCT00847106 |
Basiliximab | Glioblastoma Multiforme | I | 34 | NCT00626483 | |
Anti- CCR4 antibody | Mogamulizumab (KW-0761) | Advanced Solid Tumors + Nivolumab | I | 118 | NCT02476123 |
CCR4 inhibitor | FLX475 | Advanced Cancer + Pembrolizumab | I/II | 375 | NCT03674567 |
Gastric Cancer + Pembrolizumab | II | 90 | NCT04768686 | ||
Anti-CTLA-4 antibody | Tremelimumab | Metastatic Urothelial Cancer | II | 28 | NCT03557918 |
NSCLC + Durvalumab | II | 15 | NCT04625699 | ||
Ovarian Cancer | I/II | 50 | NCT02571725 | ||
NSCLC + Durvalumab | I | 31 | NCT03275597 | ||
Ipilimumab | Hepatocellular Carcinoma + Nivolumab | II | 40 | NCT03510871 | |
NSCLC + Nivolumab | II | 50 | NCT03262779 | ||
Renal Cell Carcinoma + Nivolumab | II | 74 | NCT03297593 | ||
Advanced Melanoma + FLX475 | II | 20 | NCT0489499 | ||
Anti-GITR agonistic antibody | BMS-986156 | Solid Tumors | I/II | 60 | NCT04021043 |
GWN323 | Solid Tumors + PDR001 | I | 92 | NCT02740270 | |
INCAGN0187 | Glioblastoma + INCAGN01876 + Stereotactic Radiosurgery | II | 32 | NCT04225039 | |
REGN6569 | Squamous Cell Carcinoma of Head and Neck + Cemiplimab | I | 85 | NCT04465487 | |
ASP1951 | Advanced Solid Tumors + Pembrolizumab | I | 436 | NCT03799003 | |
Anti-LAG-3 antibody | BMS 986,016 (Relatlimab) | Glioblastoma | I | 63 | NCT02658981 |
Sym022 | Solid Tumor | I | 15 | NCT03489369 | |
REGN3767 | Malignancies | I | 669 | NCT03005782 | |
INCAGN02385 | Melanoma + INCMGA00012 (anti-PD-1) + INCAGN02390 (anti-TIM-3) | I/II | 52 | NCT04370704 | |
Anti-LAG-3/PD-L1 antibody | IBI323 | Advanced Malignancies | I | 322 | NCT04916119 |
MGD013 | Advanced Solid Tumors | I | 353 | NCT03219268 | |
RO7247669 | Solid Tumors | I | 320 | NCT04140500 | |
Anti-TIGIT antibody | Ociperlimab (BGB-A1217) | Cervical Cancer + Tislelizumab | II | 167 | NCT04693234 |
AB154 | Glioblastoma + AB122 | I | 46 | NCT04656535 | |
Tiragolumab | NSCLC + Atezolizumab | III | 560 | NCT04294810 | |
IBI939 | NSCLC | I | 42 | NCT04672369 | |
Anti-TIGIT/PD-1 antibody | AZD2936 | NSCLC | I/II | 147 | NCT04995523 |
Anti-OX40 antibody | PF-04518600 | Metastatic Renal Cell Carcinoma + Axitinib | II | 104 | NCT03092856 |
MEDI6469 | Colorectal Neoplasms | I | 4 | NCT02559024 | |
BMS 986,178 | Solid Tumors | I | 12 | NCT03831295 | |
INCAGN01949 | Stage IV Pancreatic and Other Cancers Except Melanoma + CMP-001 | I/II | 42 | NCT04387071 | |
Anti-ICOS antibody | KY1044 | Advanced Cancer + Atezolizumab | I/II | 412 | NCT03829501 |
Feladilimab | Head and Neck Squamous Cell Carcinoma + Pembrolizumab | II/III | 314 | NCT04128696 |