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Immunotherapy: Interaction between macrophages and other immune cells.
Tumor-associated macrophages ( TAM ) are the core of immunosuppressive cells and cytokine networks, and play a vital role in tumor immune evasion. Therefore, understanding the interaction between macrophages and other immune cells and the factors that enhance existing anti-cancer treatments are crucial.
TAM is functionally heterogeneous and is divided into two main subgroups, M1 and M2 macrophages. 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 play a key role in limiting immune responses, inducing angiogenesis, and tissue repair. Therefore, the presence of M2 type TAM is related to tumor-promoting activity, and the presence of M1 type TAM is related to anti-tumor activity.
In short, TAM is the key to the production of immunosuppressive TME, and the crosstalk between macrophages and various immune cells and cytokines in TME plays an irreplaceable role.
Understanding the main mechanisms of macrophages involved in tumor immune escape and related targeted therapies will help us improve clinical programs and formulate potential new strategies for overcoming macrophage-related immune tolerance.
Signal pathway regulating macrophage phagocytosis
CD47 is an immunoglobulin widely distributed on the surface of normal cells.
It can negatively regulate anti-tumor immunity by inhibiting phagocytosis and participate in mediating cell proliferation, migration, apoptosis and immune homeostasis.
Its main ligand signal regulatory protein α ( SIRPα ) is a transmembrane protein highly expressed on the myeloid cell membrane.
The N-terminal of its extracellular domain can bind to CD47, leading to the immunoreceptor tyrosine inhibitory motif ( ITIM ) Phosphorylation of tyrosine on the tyrosine releases a “don’t eat me” signal, thereby inhibiting macrophage-mediated phagocytosis and protecting normal cells from the destruction of the immune system.
Studies have shown that CD47 is highly expressed in a variety of tumors, such as hematological malignancies and hepatocellular carcinoma ( HCC ), which is also associated with poor prognosis.
Administration of CD47 blocking antibody or targeted inactivation of CD47 gene can significantly inhibit tumor growth.
In addition, anti-CD47 therapy can also change the polarization state of macrophages in TME and induce TAM to transform into an anti-tumor state.
Leukocyte immunoglobulin-like receptor B ( LILRB ) is expressed on most immune cells and consists of an extracellular Ig-like region, a transmembrane region, and an intracellular region containing ITIM.
It can mediate the negative regulation of immune cell activation after combining with the major ligand major histocompatibility complex I ( MHCI ).
MHCI is a complex formed by HLAα chain and β2-microglobulin ( β2M ). Some tumor cells highly express β2M, which can bind to LILRB1 on macrophages to inhibit phagocytosis, leading to loss of immune surveillance.
Therefore, in patients with normal or high expression of MHC I on tumor cells, drugs targeting the MHC I/LILRB1 axis may promote anti-tumor immune responses and have a synergistic effect with drugs targeting the CD47/SIRPα axis.
CD24, also known as thermostable antigen, is a highly glycosylated surface protein anchored by glycosyl phosphatidylinositol, which can interact with sialic acid-binding immunoglobulin-like lectin-10 ( Siglec-10 ) To reduce harmful inflammation mediated by innate immunity caused by infection or liver damage.
Tumor cells highly express CD24, while TAM highly express Siglec-10.
After binding to CD24, the ITIM of Siglec-10 can recruit and activate the SH2 domain-containing tyrosine phosphatase SHP-1 or SHP-2, thereby blocking the cytoskeletal rearrangement required for macrophage phagocytosis and triggering inhibitory properties Signal transduction cascade.
“Don’t eat me” sends out CD47, β2M and CD24 signals, all of which involve ITIM-based macrophage signals, leading to immune selection of drug-resistant cancer cell subgroups of macrophages, allowing tumor cells to evade the surveillance and monitoring of macrophages.
Therefore, understanding the mechanism by which tumor cells express anti-phagocytic signals can better predict the therapeutic effect and targeted therapy.
Macrophages are involved in the mechanism of immune evasion
Macrophages participate in the formation of an inhibitory myeloid microenvironment
Various mediators in TME participate in regulating the recruitment of MDSC and monocytes, and polarize macrophages through different signaling pathways, thereby promoting the formation of the immunosuppressive myeloid microenvironment.
In addition, the crosstalk between macrophages, MDSCs and dendritic cells further forms an immunosuppressive myeloid microenvironment.
Ovarian cancer cells highly express CD39 and CD73, which help to catalyze the conversion of extracellular ATP into adenosine, which can recruit monocytes and induce them to differentiate into IL-10 secreting TAM.
TAM expresses CD39 and CD73, which further increases the infiltration of MDSC and TAM, thereby forming a self-amplification mechanism to promote local immune escape.
Tumor-associated neutrophils ( TAN ) are also an important part of the immunosuppressive myeloid microenvironment. Like macrophages, neutrophils can be described as two subpopulations, N1 and N2.
N1 shows anti-tumor activity, and N2 is thought to promote tumor metastasis. In breast cancer models, IL-1β secreted by TAMs induce γδT cells to release IL-17 to regulate the release of G-CSF and promote the recruitment of neutrophils to stimulate metastasis, indicating that TANs are closely related to TAMs in tumor progression.
However, the specific interaction mechanism of TAN and TAM in tumorigenesis and immune escape is still unclear.
Macrophages affect Th cells
There is mutual regulation between macrophages and helper T cells. Macrophages rely on TGF-β and IL-10 to transform Th1 cells into Th2 cells to reverse the anti-tumor effects of CD8+ cytotoxic T cells and CD4+ Th1 cells, which is considered to be a tumor immune escape mechanism.
Th cells affect tumor TME by changing the polarization direction of macrophages. Th1 cells secrete IFN-γ to induce M1 polarization, while Th2 cells can secrete IL-4, IL-5 and IL-10 to promote the production of M2 macrophages.
In addition, Treg phenotype and function play an important role in immunosuppressive TME. Recent studies have shown that macrophages can affect the proliferation, migration and function of Treg through various ways.
First, TAMs can secrete IL-23, promote the proliferation of Tregs and the expression of IL-10 and TGF-β, and inhibit CTL killing tumor cells.
Second, macrophages overexpress CCL1, which is the ligand of CCR8 expressed on Tregs.
Attract Treg into the tumor area; similarly, macrophages secrete CCL22 to induce Treg to migrate to the tumor area of ovarian cancer, suppress T cell immunity and promote tumor growth.
Interaction between macrophages and CAF
CAF is the most abundant stromal cell in TME, which can release a large number of cytokines, synthesize and reshape the extracellular matrix, and form a tumor-promoting fibrous microenvironment.
CAF can secrete IL-6, M-CSF, MCP-1 and stromal cell-derived factor-1 to promote the infiltration and differentiation of macrophages.
M2 can secrete TGF-β to promote the transformation of endothelial cells to mesenchymal cells and increase the reactivity of CAF, thereby enhancing the invasiveness of cancer cells.
Macrophages mediate immune escape via the PD-1/PD-L1 axis
TAMs regulate the expression of PD-L1 on tumor cells and PD-1 on CD8+ T cells. PD-L1 is highly expressed in a variety of tumor tissues, can be up-regulated by TAM-derived TNF-α, and is positively correlated with macrophage infiltration in tumor stroma.
In TME, the expression of PD-L1 on TAMs is also affected by many factors. The IL-27/STAT3 axis induces PD-L1/2 overexpression in lymphoma infiltrating macrophages.
Progranulin can up-regulate PD-L1 on TAMs through the STAT3 pathway, thereby promoting immune evasion of breast cancer.
At the same time, the PD-1/PD-L1 axis has a profound effect on the function of macrophages. The increase of PD-1 expression on TAMs can inhibit its phagocytosis, and structurally act on the mTOR pathway, and negatively regulate the proliferation and activation of macrophages. Therefore, PD-1/PD-L1 blockade can also directly affect macrophages.
PD-1/PD-L1 blockers can promote the pro-inflammatory polarization of macrophages, enhance the activity of effector T cells, and cooperate with other immune checkpoint inhibitors to limit tumor spread.
In addition to the PD-1/PD-L1 axis, some experimental results indicate that TAM can also induce immune escape with other immune checkpoints ( such as the CTLA/CD86 axis and the TIM3/galectin-9 axis ), but there is still a lack of definite evidence.
The interaction between macrophages and these immune checkpoints in immune escape is worthy of further study.
Macrophages help to form immune non-reactive sites
Immune non-response is an important reason for tumor tissues to evade immune surveillance. Macrophages may participate in the immune exemption of tumor tissues through the following mechanisms.
First, macrophages can accumulate CAF to the tumor area, CAF deposits fibrous collagen, hyaluronic acid, fibronectin and other substances, and secretes lysyl oxidase to stimulate type I collagen cross-linking, thereby forming a physical barrier.
Secondly, similar to tumor cells, induced TAM can express Fas-L and release active soluble Fas-L, and induce Fas+ lymphocyte apoptosis, while CAF can up-regulate Fas-L and PD-L2 through MHC-1 antigen cross-presentation, and inhibit CD8+ T cell activity, thereby forming TME lacking lymphocyte infiltration.
In addition, hyaluronic acid secreted by tumor cells can bind to TLR4 on the surface of macrophages, induce TAM to migrate to tumor-related areas, and inhibit the expression of C/EBPβ through miR935, promote the differentiation of macrophages to the M2 phenotype, thereby promoting Malignant tumor cells evade immune surveillance and “cool down” the immune response.
Clinical progress of macrophage immunotherapy
More and more evidences show that TAM contributes to chemotherapy resistance. Monotherapy or combination chemotherapy with TAM as the target is undergoing preclinical and clinical trials.
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 that targets 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 is used in combination with paclitaxel in patients with advanced solid tumors ( NCT01525602 ); PLX3397 is used in a trial with eribulin in breast cancer patients ( NCT01596751 ); PLX3397 and vemurafenib are used in BRAF-mutated melanoma patients ( NCT01826448 ); PLX3397 is used in combination with sirolimus Patients with advanced sarcoma ( NCT02584647 ) and so on.
In addition, the combined application of TAM targeting agents and immune checkpoint inhibitors is also under development.
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 and pembrolizumab in various tumor patients ( NCT02452424 ), a combination 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 ).
Until November 2020, two clinical trials based on the CAR-M strategy have been approved by the FDA. The first is the drug candidate CT-0508 from CARISMA Therapeutics , which uses anti-HER2 CAR-M to treat patients with relapsed/refractory HER2 overexpression tumors ( Phase I clinical trial ). The other is Maxyte’s MCY-M11 , which uses mRNA to transfect PBMC to express CAR ( including CAR-M ) targeting mesothelin to treat patients with relapsed/refractory ovarian cancer and peritoneal mesothelioma. It is currently recruiting volunteers Conduct Phase I clinical trials.
More and more studies have shown that macrophages play a key role in tumor development, metastasis, immune regulation, tumor angiogenesis, TME remodeling and cancer treatment response.
Macrophage targeted therapy is expected to become the next frontier of tumor immunotherapy.
The clarification of its interaction mode will help to form a more comprehensive understanding of immunosuppressive TME, avoid immune rebound, reduce tumor immune evasion, and promote the development of related research .
1.Next frontier in tumor immunotherapy:macrophage-mediated immune evasion. Biomark Res. 2021; 9: 72.
Immunotherapy: Interaction between macrophages and other immune cells,
(source:internet, reference only)