Table 1.
Innate Immune Cells in the Tumor Microenvironment
| Cell Type | Normal Functions | Stimulatory Cytokines in the TME |
Cytokine/ Chemokine Secretion |
Human Markers | Mouse Markers | Effect | Source (s) |
|---|---|---|---|---|---|---|---|
| MACROPHAGES | |||||||
| M1 | Activate Th1 responses, phagocytosis, Type 4 hypersensitivity | IFN-γ | IL-12, IL-23, IL-1β, IL-6, IL-12, IL-23, CCL10, CCL11, CCL2-5, CCL8, CCL9 | CD64, IDO, SOCS1, CXCL10, CD80, CD86, CD68, MHC-II, IL-1R, SOCS3 | CXCL9, CXCL10, CXCL11, NOS2 | Anti-tumor | [2, 13] [93] |
| M2a | Activate Th2 responses, wound healing, allergy | IL-4, IL-10, IL-13, CSF1, CCL2, CCL3, CCL14 | IL-4, L-arginine, PGE2, IL-10, TGF-β, IL-1ra, CCL17, CCL22, CCL24 | MRC1, TGM2, CD23, CCL22, CD163, IL-1R II | Mrc1, Tgm2, Fizz1, Ym1/2, Arg1, MHC-II, IL-1ra | Pro-tumor | [2, 13] [93] |
| M2b | Th2 activation, immunoregulation | TLR agonists, Immunocomplex | IL-1, IL-6, IL-10, TNF-α, CCL1 | CD86, MHC-II | CD86, MHC-II | Pro-tumor | [13] [93] |
| M2c | Tissue repair, immunoregulation, matrix remodeling | IL-10, TNF-α, Glucocorticoids | TGF-β, IL-10, CCR2 | CD163, Mrc2 | CD163, Mrc1 | Pro-tumor | [13] [93] |
| M2d | Angiogenesis, clearance of apoptotic tissues | TLR, adenosine A2A receptor | TNF-α, TGF-β, VEGF-A, IL-10, IL-12, CCL5, CXCL10, CXCL16 | VEGF | VEGF | Pro-tumor | [13] [93] |
| DENDRITIC CELLS | |||||||
| Immature DCs | Recognize antigens, migrate to secondary lymphoid organs, phagocytosis, minimal APC, induce T cell anergy and promote Th2 and T-reg responses | N/A | N/A | CD11c, HLA-DR, FLT3L | Cd11c, MHCII, FLT3L, CD45 | Depends on tumor type | [20, 94] |
| cDC1 | APC to CD8 T cells, cross presentation, secretion of IL-12 | IL-12, TNF-α, IFN-γ | CD11c, CD141, XCR1, HLA-DR, Necl2, CLEC9A, CD80, CD86, CD40, CCR7, FLT3, TLR3, CD103, CADM1, CD26, BTLA, CD226, CD13 CD33, CXCR3, CXCR4 CLEC9A | CD11c, CD8α (lymphoid), MHCII, Clec9A, CD103 (Non-Lymphoid), DEC205, XCR1, CD80, CD86, CADM1, CD26, CD24 | Depends on tumor type | [19, 95-97] | |
| cDC2 | APC to CD4 T cells | TGF-β, IL-6, IL-8, IL-1, IL-12, IL-23, IL-10, TNF-α | CD11c, HLA-DR, CD1c, CD11b, CD80, CD86, FLT3, CLEC7A, CLEC6A, Dectin 1&2, CD40, CADM1, CD172a, CD2, SIRPA, FceR1, DCIR, CD62L, MHCII, ILT1 | CD11c, CD11b, MHCII, CD4 +/−, Sirpa+, CD80, CD86, CD172a, CD26 | Depends on tumor type | [19, 95-97] | |
| pDCs | Abundant secretory activity (IFN type 1), respond to viral infections | Type 1 IFN, TNF, IL-6 | CD11c, HLA-DR, CD304, CD303, CD123, FLT3, B220, PDCA1, FceR1, ILT3, ILT7, DR6, CD300A, BTLA, CD62L, CD45RA | CD11c, B220, CD45, Siglec H, CD317, Gr-1, Ly6C | Depends on tumor type | [20, 95-97] | |
| MoDCs | Produce high levels of the pro-inflammatory cytokines TNF, IL-6, and IL-12 | TNF-α, IL-1, IL-12, IL-23 | CD11c, CD14, Factor XIIIA, HLA-DR, CD62L, CXCR3, CD209, CD1c, CD80, CD86, CD64, MAR-1 | CD11c, MHC-II, CD11b, F4/80, Ly6C, CD206, CD115, CD107b, FcεRI, CD80, CD86 | Anti-tumor | [19, 94, 96, 98, 99] | |
| Tolerogenic DCs | Diminished APC, stimulate Th2 responses and Tregs to induce tolerance | PGE2, TGF-β, VEGF, IL-10, TNF-α | TGF-β | C1QA, C3AR1, CD163, CD300LF, CFH, CSGALNACT1, FcyR11A, FcyR11B, P2RY14, ZBT16 | SLAM, PDL1, PDL2, DEC205, IDO | Pro-tumor | [98-100] |
| NEUTROPHILS | |||||||
| N1 | Phagocytosis; release of NETs, inflammatory cytokines, toxin and ROS; respiratory burst, promotion of tumor cell apoptosis | N/A | TNF-α, IL-1, IFNs, MMP-8, Defensins, Along with toxic substances and reactive oxygen species. | TNF-α, I-CAM1, FAS, ROS | TNF-α, I-CAM1, FAS, ROS | Anti-tumor | [23, 30, 33] |
| N2 | Support angiogenesis, cancer cell migration and invasion, immune surveillance, and metastasis as well as secrete chemokines, cytokines and ROS/RNS | TGF-β, Angiotensin II | Oncostatin-M, MMP-9, CXCL1, CXCL8, CCL-3, Neutrophil elastase (NE), CXCL6, Collagenase IV, Heparanase, TGF-β, PGE2 | Arginase, CCL2, CCL5 | Arginase, CCL2, CCL5 | Pro-tumor | [23, 30, 33] |
| MYELOID DERIVED SUPPRESSOR CELLS | |||||||
| M-MDSCs | Suppress innate and adaptive immune responses | CSF-1, CCL2, CCL7, HIf1α, CXCL1 | NO, CCL3, CCL4, CCL5, Arg1, PGE2, IL-4 | CD11b+, HLADRlo/−, CD14+ | Cd11b+. Ly6Chi, CD49d+ | Pro-tumor | [41-43] |
| PMN-MDSCs | Suppress innate and adaptive immune responses | ROS, Arg1, PGE2, IL-4 | CD11b+, HLADR−, CD15+, CD14− | Cd11b+, Gr-1hi, Ly6G+, Ly6Clo | Pro-tumor | [41-43] | |
| eMDSCs | Suppress innate and adaptive immune responses | N/A | CD33+, Lin−, CD13−, CD14− CD3−, CD6− | Not well characterized | Pro-tumor | [42] | |
| NATURAL KILLER CELLS | |||||||
| CD56hi CD16+/− NKs |
Produce inflammatory cytokines | TGF-β, PGE2, IDO, IL-10 | IFN-γ, TNF-α | CD16+/−, CD56, NKG2A, CCR7, CXCR, CXCR3 | NKp46, NK1.1, CD122 | Depends on tumor type | [48, 51] |
| CD56lo CD16hi NKs |
Promote antibody dependent cellular cytotoxicity, high perforin production, enhanced killing | TGF-β, PGE2, IDO, IL-10 | IL-22, IL-10 | CD16hi, perforinhi | Not well characterized | Depends on tumor type | [48, 51] |
| INNATE LYMPHOID CELLS | |||||||
| ILC1 NK Cells | Cytotoxicity, macrophage activation, chronic inflammation, CD8 T cell activation | N/A | IFN-γ, TNF-α | CD56, NKp46, NKp44, IL/12RB2, DNAM1 | CD56, NKp46, NKp44, IL/12RB2, CD161, TIGIT, CTLA-4, CD96, NKG2A | Anti-tumor | [57, 62] |
| ILC1 Non-NK | Macrophage activation, chronic inflammation | N/A | IFN-γ, TNF-α | ICOS, IL-1R, IL/12RB2, CCR6 | ICOS, IL-1R IL/12RB2 | Anti-tumor | [57, 62] |
| ILC2 | Stimulate T cell responses through Th2 related cytokines, promotes skin inflammation | IL-33, IL-25 | IL-5, IL-13, | CD117, CD127, ICOS, CD294, IL-1R, ST2, IL-17RB, CD161, NKp30, PD1, CRTH2 | CD127, ICOS, CD294, IL-1R, ST2, IL-17RB, Sca1, PD1, CRTH2 | Pro-tumor and anti-tumor | [57, 62] |
| ILC3 | Chronic inflammation, intestinal homeostasis, lymphoid development bacterial immunity, | IL-23, IL-1β | IL-22, IL-17, GM-CSF | CD127, CD117, CD25, IL-1R, ICOS, IL-23R, MHCII, CCR6, NKp44, NKp30, NKp46, CD161 | CD127, CD117, CD25, IL-1R, ICOS, IL-23R, Sca1, MHCII, NKp46, CD161 | Pro-tumor | [57, 62] |
N/A: Not Applicable