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Do Heterogeneous myeloid cells in tumors inhibit or promote tumor development?
Do Heterogeneous myeloid cells in tumors inhibit or promote tumor? Myeloid cells play a key role in regulating the behavior of lymphocytes, leading to immunostimulatory or immunosuppressive TME, thereby inhibiting or promoting tumor development.
As we all know, lymphocytes play a key role in tumor immune surveillance. And more and more evidence shows that myeloid cells also have a great influence on the development of tumors. Tumor-associated myeloid cells (TAMC) are heterogeneous and have obvious or even opposite effects on tumor cells and tumor microenvironment (TME). In addition, myeloid cells play a key role in regulating the behavior of lymphocytes, leading to immunostimulatory or immunosuppressive TME, thereby inhibiting or promoting tumor development.
The most studied TAMCs include:
- monocytes, tumor-associated macrophages (TAMs),
- dendritic cells (DC),
- tumor-associated neutrophils (TANs),
- myeloid-derived suppressor cells (MDSC).
They are involved in pleiotropic processes, including tumor cell growth, survival, differentiation, dissemination and metastasis, angiogenesis, TME remodeling, immune regulation, and response to cancer treatment. Understanding the role and mechanism of TAMCs in tumors will help discover new treatments.
Monocytes are a group of heterogeneous mononuclear phagocytes that exert innate immune function in circulating peripheral blood during inflammation. Most circulating monocytes are classical monocytes expressing CD14+CD16- in humans and Ly6Chigh cells in mice. Differentiated from common monocyte progenitor cells (cMoP), classical monocytes leave the bone marrow by expressing chemokine receptors and following a chemokine gradient, such as CCL2 and CCL7. In the steady-state process, the circulating classic monocytes transform into intermediate monocytes, express CD14+CD16+ in humans, Ly6Cint in mice, and then transform into non-classical monocytes, in humans It expresses CD14lowCD16+, and expresses Ly6Clow in mice. After infection, classical monocytes will rapidly exudate the inflamed tissues, respond to chemokines, cytokines, and complement fragments, and mediate antibacterial effects, such as phagocytosis.
In different stages of tumor development, different monocyte subpopulations show different or even opposite effects.
IFN-γ or IFN-α can up-regulate the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in human monocytes and down-regulate the expression of TRAIL receptor 2. TRAIL mediates tumor cell apoptosis without damaging monocytes . After being stimulated by tumor cells, human CD14+CD16+ monocytes increase the production of pro-inflammatory cytokines TNF-α and IL-12, reduce the production of anti-inflammatory cytokine IL-10, and have direct ADCC effects on tumor cells toxicity.
In addition, non-classical monocytes mediate the cytotoxicity of regulatory T cells (Treg) in vitro in an Fcγ-dependent manner. Circulating monocytes in patients with renal cell carcinoma (RCC) and mouse models show the characteristics of tumor-promoting genes, and the expression of pro-angiogenic factors IL-8, vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MPPs) are up-regulated. Functional studies have shown that the culture medium derived from renal cell carcinoma monocytes promotes angiogenesis by blocking VEGF receptor 2 (VEGFR2), which indicates that monocytes in renal cell carcinoma have VEGF-dependent pro-angiogenic properties, and through heavy Plastic TME promotes tumor cell invasion.
In terms of mechanism, classic monocytes produce VEGF, which promotes tumor cell extravasation and leads to metastasis. In contrast, non-classical monocytes are activated after engulfing tumor cell-derived particles, thereby reducing tumor cell metastasis. This indicates that classic monocytes have a metastasis-promoting effect, while non-classical monocytes have an anti-metastatic effect.
TAM is functionally heterogeneous and is divided into two main subgroups, M1 and M2 macrophages. In response to lipopolysaccharide (LPS), IFN-γ and GM-CSF, M1 macrophages undergo classic activation and preferentially secrete antibacterial molecules and pro-inflammatory cytokines, including reactive oxygen species (ROS) and nitric oxide (NO) And IL-6. M1 macrophages are the first line of defense against microbial infections. M1 macrophages also maintain a strong antigen presentation ability and induce a strong Th1 response.
In contrast, M2 macrophages undergo selective activation by IL-4, IL-13, IL-10 and CSF-1, and preferentially secrete anti-inflammatory cytokines, including transforming growth factor β (TGF-β), IL- 10 and proteases (such as arginase-1 and MPPs). M2 macrophages play a key role in limiting immune responses, inducing angiogenesis and tissue repair. Therefore, the presence of M2-like TAM is related to tumor-promoting activity, and the presence of M1-like TAM is related to anti-tumor activity.
TAM creates a mutagenic microenvironment that is conducive to tumor initiation by secreting pro-inflammatory mediators, such as TNF-α and ROS.
In patients with non-small cell lung cancer, the expression of immune checkpoint ligand PD-L1 is up-regulated in tumor-infiltrating immune cells, which are rich in M2-like TAM. Mechanism studies have shown that after exposure to lactic acid, the expression of PD-L1 on TAMs is up-regulated. The interaction of PD-L1 and PD-1 on T cells inhibits T cell proliferation and induces T cell apoptosis, leading to immune tolerance. At the same time, TAM inhibits the expansion of CD4+ helper T cells by expressing PD-L1 and secreting the anti-inflammatory cytokine IL-10.
In addition, TAM recruits Tregs by secreting the chemokine CCL22, and enhances the functions of Tregs by secreting TGF-β. Human TAM also secretes epidermal growth factor (EGF) to enhance the aggressiveness of tumor cells. TAM all up-regulate MMP, MMP degrades interstitial collagen, and up-regulates the synthesis and assembly of collagen to reshape TME, which is conducive to tumor cell invasion.
Dendritic cells are the most effective antigen presenting cells (APCs), connecting innate immunity and adaptive immunity. DC has phenotypic and functional heterogeneity under physiological conditions. As a response to microbial infections, extracellular microbial proteins are usually phagocytosed or endocytosed by mature DCs, and are presented to CD4+ T cells through Class II major histocompatibility complex (MHC) molecules. In contrast, cytoplasmic microbial proteins are usually presented to CD8+ T cells through class I MHC molecules. The DCs that penetrate into TME include different subpopulations at different developmental stages. These tumor-associated dendritic cells exert immunostimulatory or immunosuppressive effects according to dendritic cell subgroups and tumor stages.
Traditional DC (cDC)
cDC is composed of two subgroups with different phenotypes and functions. Human cDC1 expresses CD11c, MHC-II, BDCA3, CD141, XCR1, CLEC9A and DNGR1. Human cDC1 expresses toll-like receptors (TLR) and secretes pro-inflammatory cytokines, including IL-12p70 and IFN-α, to induce Th1 responses in response to infection. cDC1 stimulates the anti-tumor immune response, and cDC1 specific gene markers have been used as positive prognostic markers for cancer patients. The presence of cDC1 in tumors is associated with good clinical outcomes.
cDC2 is more abundant, expressing CD11c, MHC-II, BDCA1, CD172a (SIRPα), CD115 (CSF-1R) and CD11b. Human cDC2 produces various cytokines, such as IL-10 and IL-23, and presents antigens to CD4+ helper T cells, thereby activating effector T cells, including Th2 cells and Th17 cells. cDC1 activates CD8+ T cells in different regions of dLN, while cDC2 activates CD4+ T cells in different regions of dLN. Although the effector T cells activated by cDC2 are mainly Tregs that cause immune tolerance, the expression of cDC2 gene markers is associated with a positive prognosis in human and mouse models. Therefore, both cDC1 and cDC2 are conducive to anti-tumor immunity.
Plasma cell-like DC (pDC)
DCs that have the same morphology as plasma cells that secrete antibodies are called pDCs. Human pDC is CD123+CD303+CD304+CD11c−. In response to viral infection, pDC recognizes viral nucleic acid through TLR, secretes type I interferon IFN-α, and plays a key role in antiviral defense. However, tumor-infiltrating pDC can reduce IFN-α and maintain the expansion of FoxP3+Tregs in the body, which promotes immune tolerance and tumor progression. In addition, pDCs in melanoma patients express indoleamine 2,3-dioxygenase, which can consume tryptophan, leading to T cell anergy and immune tolerance. Show that pDC can induce immunosuppressive immune response.
In addition to immunosuppressive effects, some studies have shown that pDC can induce immunostimulatory responses. CD123+pDC is located in the peritumoral area of primary melanoma and is in close contact with CD8+ T cells. Functional analysis showed that both human and mouse pDC can stimulate CD8+ T cells, leading to their activation and differentiation into cytolytic and IFN-γ effector T cells, and tumor regression in vivo.
TME’s human CD2highpDC expresses high levels of granzyme B, TRAIL and lysozyme, which limit the proliferation of tumor cells and mediate the contact-dependent killing of tumor cells. In addition, CD2highPDC can also effectively secrete IL-12p40, which can stimulate naive T cells, leading to T cell expansion and immune response. Therefore, pDC plays both a tumor-promoting effect and an anti-tumor effect in the process of tumor development.
Monocyte-derived DC (MoDC)
In response to infection, circulating monocytes enter tissues and differentiate into DCs. These DCs are called MoDCs or inflammatory DCs (inf DCs), which express CD1a, BDCA1, CD11c, MHC II, and CD64 in humans. MoDC has been observed in TME of certain cancers. MODC can effectively express TNF-α and inducible nitric oxide synthase (iNOS). NO produced by iNOS can inhibit T cell proliferation, indicating that MoDCs induce immunosuppressive response. In addition, in the mouse model of lymphoma, the adoptively transferred CD8+ T cell-mediated anti-tumor effect depends on the nitric oxide synthase 2 (NOS2) expressed by DC, suggesting that MODC has an immunostimulatory effect. Therefore, the function of MoDC in tumors needs further study.
Cancer-related circulating neutrophils
Neutrophils are polymorphonuclear phagocytes that have natural immune function against microbial pathogens in the peripheral blood circulation. In cancer patients, especially at advanced stages and after metastasis, the number of circulating neutrophils increases, and high neutrophil to lymphocyte ratio (NLR) is associated with aggressive outcomes.
These cancer-related circulating neutrophils include functionally heterogeneous subpopulations. High-density neutrophils (HDN) are a group of homogeneous mature neutrophils that express CD66b, CD11b, CD15, CD16 and CD10 in humans. Low-density neutrophils (LDN) are a group of heterogeneous cells with two main subpopulations based on developmental stages, namely, mature neutrophils derived from HDN and immature MDSCs. In tumor-free mice, more than 95% of circulating neutrophils are HDN. In tumor-bearing mice, such as breast cancer, mesothelioma, and lung cancer, the number of circulating neutrophils (especially LDN) increases as the tumor progresses.
CD11b+MMP+HDN accumulates in the lungs before tumor metastasis and mediates direct cytotoxicity against tumor cells by releasing ROS. In contrast, LDN showed reduced production of reactive oxygen species, no cytotoxicity to tumor cells, and no significant effect on initial tumor growth. Mechanism studies have shown that LDN induces supportive TME by down-regulating the expression of pro-inflammatory cytokines and restricting the proliferation of CD8+ T cells. This indicates that HDN has an anti-tumor effect, while LDN has a tumor-promoting effect.
Tumor-associated neutrophils (TAN)
In addition to circulating neutrophils associated with tumors, TAN also plays a key role in tumor development and metastasis.
A number of studies have shown that TAN in TME promotes the proliferation, extravasation and migration of tumor cells. TAN can release particulate components, such as elastase, to promote the proliferation and invasion of cancer cells. TAN also promotes the extravasation of tumor cells to the metastatic niche by secreting IL-1β and MPPs, thereby promoting the spread of cancer cells. In addition to promoting tumor effects, TAN also mediates the cytotoxicity of tumor cells by producing ROS and TRAIL.
Neutrophils with anti-tumor effects are called “N1” TAN, and neutrophils with tumor-promoting effects are called “N2” TAN. Studies have shown that TME affects the balance of N1 and N2 subgroups by secreting various cytokines. For example, TGF-β, IL-6, G-CSF and IL-35 can induce the pro-tumor polarization of TAN, IFN-β and IL -12 can induce the anti-tumor polarization of TAN. Studies have also shown that TAN interacts with lymphocytes in TME and regulates its function. In 4T1 tumor-bearing mice, N2 TAN inhibited tumor cell clearance mediated by NK cells, thereby promoting tumor metastasis. N2 TAN also recruits Tregs into TME by secreting CCL17, thereby promoting tumor growth. In contrast, N1 TAN produces chemokines, such as CCL3, CXCL9, and CXCL10, recruits CD8+ T cells into TME, and secretes cytokines (such as IL-12, TNF-α, and GM-CSF) to activate CD8+T Cytotoxicity of cells, thereby providing anti-tumor effects.
Other types of granulocytes
In addition to neutrophils, other types of granulocytes, such as eosinophils and basophils, can also affect tumors. The role of eosinophils in fighting worm infections and allergic diseases is well known. In vitro, human and mouse eosinophils show direct cytotoxicity to various cancer cells. In addition, eosinophils also show indirect cytotoxicity to cancer cells by secreting pro-inflammatory cytokines (such as TNF-α). Cytotoxicity indicates that eosinophils have anti-tumor activity.
The growth of basophils in patients with chronic myelogenous leukemia (CML) is associated with poor prognosis and AML transformation. Mechanism studies have shown that basophils secrete hepatocyte growth factor (HGF), which leads to the expansion of CML cells. These studies have shown that basophils may participate in the evolution of the disease into high-risk hematological malignancies. On the other hand, melanoma patients with high levels of basophils showed better overall survival rates after immunotherapy, indicating that basophils have anti-tumor potential. Therefore, the role of basophils in tumors is still unclear, and more research is needed.
Myeloid-derived suppressor cells
MDSCs are a group of heterogeneous myeloid progenitor cells and immature myeloid cells at different developmental stages. Human MDSCs express CD14−, CD11b+, CD33+ and MHC class II−. In cancer patients, the number of circulating MDSCs increases, and the infiltration of MDSCs in TME is associated with poor prognosis.
MDSC plays various tumor-promoting effects in the process of tumor progression and metastasis. MDSCs can enhance tumor stem cells and provide pro-survival signals for tumor cells. MDSCs accumulated in TME produce MMP9, which promotes tumor growth and tumor vasculature. MDSC also secretes and produces TGF-β, EGF and HGF to induce epithelial-mesenchymal transition (EMT) and promote the spread of cancer cells.
The main feature of MDSC is to suppress the function of immune cells, with emphasis on T cells. MDSCs inhibit the proliferation and function of T cells by down-regulating the expression of IL-2, INF-γ and granzyme B. MDSCs can also reduce the number of antigen-specific CD8+ T cells and inhibit the cytotoxicity of CD8+ T cells. MDSC restricts the cysteine supply of T cells by isolating cysteine from the extracellular space, thereby inhibiting the expansion of T cells. MDSC also destroys the binding of T cell receptor and MHC antigen complex by nitrating TCR/CD8, resulting in T cell incompetence.
MDSC consists of two main subgroups. Granulocyte MDSCs (GrMDSCs) and monocyte MDSCs (MoMDSCs). GrMDSCs are similar in phenotype and morphology to neutrophils, expressing CD11b+CD33+CD14-CD15+. In tumor-bearing mice, GrMDSCs showed a lower level of phagocytosis, but arginase-1, myeloperoxidase (MPO) and reactive oxygen species were activated or produced at higher levels, thereby inhibiting T cell function.
MoMDSCs are similar to monocytes in phenotype and morphology, and express CD14+HLA-DRlow in humans. Compared with monocytes, MoMDSC shows high levels of arginase-1 and NO activation or production, NO damages IL-2 downstream signaling pathways, including JAK3/STAT5, ERK and AKT, thereby inhibiting the activation of T cells And proliferation.
Both GrMDSCs and MoMDSCs inhibited CD8+T cell proliferation driven by ovalbumin, indicating an antigen-specific immunosuppressive effect. Blocking IFN-γ can completely reverse the inhibitory effect of GrMDSCs on T cells, but only partially reverse the inhibitory effect of MoMDSCs on T cells, indicating that GrMDSCs mediate immune suppression in an IFN-γ-dependent manner. Inhibition of iNOS partially reversed the inhibitory effect of MoMDSC on T cells, but did not change the inhibitory effect of GrMDSCs on T cells, indicating that MoMDSC inhibited T cell proliferation through IFN-γ and iNOS/no pathways. In addition, MoMDSC-differentiated macrophages inhibited CD8+ T cell proliferation driven by anti-CD3 antibodies, indicating antigen non-specific immunosuppression. In short, both GrMDSCs and MoMDSCs contribute to the immune suppression of T cells.
TAMC in cancer treatment
There is increasing evidence that TAMCs contribute to chemotherapy resistance. Monotherapy or combination chemotherapy with TAMC as the target is undergoing preclinical and clinical trials. Among the heterogeneous populations of TAMC, TAMs and MDSC are mainly tumor-promoting and immunosuppressive, so they are being tested in different tumors.
TAM is recruited into TME by CSF-1 to promote the development and metastasis of breast cancer. Therefore, therapies using monoclonal antibodies or small molecule compounds to target the CSF-1/CSF-1R axis are being tested. RG7155 is a monoclonal antibody targeting CSF-1R. In a phase 1 clinical trial (NCT01494688), 7 patients diagnosed with diffuse giant cell tumor were treated. All patients developed PR and 2 patients developed PR. CR. In addition, in the tumor biopsy of patients treated with RG7155, the number of CD68+CD163+ macrophages was reduced, indicating that TAM recruitment to TME was reduced.
PLX3397, a tyrosine kinase inhibitor targeting CSF-1R, c-Kit, and Flt3, blocks tumor progression by depolarizing the M2 phenotype of TAM. PLX3397 is undergoing clinical trials in patients including melanoma (NCT02071940, NCT02975700), prostate cancer (NCT0149043) and glioblastoma (NCT01349036). Other CSF-1R inhibitors, such as ARRY-382 (NCT01316822), BLZ945 (NCT02829723), AMG820 (NCT01444404) and IMC-CS4 (NCT01346358) are also being tested in various solid tumor patients.
In addition to monotherapy, inhibitors against CSF-1 or CSF-1R are also tested in combination with chemotherapy. For example, PLX3397 and paclitaxel are used in patients with advanced solid tumors (NCT01525602); PLX3397 and eribulin are used in breast cancer patients (NCT01596751); PLX3397 and vemurafenib are used in BRAF-mutated melanoma patients (NCT01826448); PLX3397 and sirolimus are used in Patients with advanced sarcoma (NCT02584647) and so on.
More and more studies have shown that TAMC such as MDSC and TAM can help resist immune checkpoint inhibitors, and treatments for the development, recruitment and function of MDSC and TAM may increase the sensitivity to checkpoint inhibitor treatment.
CXCR2 is the main chemokine receptor that recruits MDSC to TME. Inhibition of CXCR2 can reduce the infiltration of MDSC into TME, thereby enhancing the anti-tumor effect. SX-682 is an inhibitor of CXCR1/2. SC-682 is being combined with nivolumab for the treatment of patients with metastatic pancreatic ductal adenocarcinoma (NCT04477343). In addition, SC-682 is also used in combination with the anti-PD-1 monoclonal antibody pembrolizumab for patients with metastatic melanoma (NCT03161431).
In addition to targeting MDSCs, it also targets TAM recruitment by inhibiting the CSF-1/CSF-1R axis. The clinical trial of IMC-CS4 in combination with durvalumab or tremelimumab for patients with solid tumors (NCT02718911) is ongoing. There is also a phase 1 clinical trial of PLX3397 combined with pembrolizumab in various tumor patients (NCT02452424), a combined trial of ARRY-382 and pembrolizumab (NCT02880371), and a combination of BLZ945 and PDR001 (a monoclonal antibody against PD-1) The trial (NCT02829723), the combined trial of RG7155 and atezolizumab (NCT02323191), and the combined trial of AMG820 and pembrolizumab (NCT02713529).
More and more studies have shown that TAMCs play a key role in tumor development, metastasis, immune regulation, tumor angiogenesis, TME remodeling and cancer treatment response. Regulating the development, maturation and function of these myeloid cells can help discover new therapeutic strategies.
However, due to the complexity and variability of various subpopulations, these myeloid cells often perform overlapping or opposite functions. In addition, the molecular mechanism that controls the behavior of TAMCs is still unclear. Future research should focus on further elucidating the functions of various subgroups of myeloid cells in different cancers and determining the molecular mechanisms related to their tumor-promoting and anti-tumor activities.
(source:internet, reference only)