April 12, 2024

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How do Tumor-associated macrophages ( TAMs ) work in tumor immunotherapy?

How do Tumor-associated macrophages ( TAMs ) work in tumor immunotherapy?



 

How do Tumor-associated macrophages ( TAMs ) work in tumor immunotherapy?

Tumor-associated macrophages ( TAMs ) are central to the network of immunosuppressive cells and cytokines that play a crucial role in tumor immune evasion.

Therefore, understanding the interactions between macrophages and other immune cells and the factors that enhance existing anticancer treatments is critical.

 

TAMs are functionally heterogeneous and divided into two major subpopulations, M1 and M2 macrophages.

M1 macrophages are the first line of defense against microbial infection. M1 macrophages also maintain a strong ability to present antigens and induce a strong Th1 response.

In contrast, M2 macrophages play a key role in limiting immune responses and inducing angiogenesis and tissue repair.

Thus, the presence of M2-type TAMs correlates with pro-tumor activity, whereas the presence of M1-type TAMs correlates with anti-tumor activity.

 

In summary, TAMs are key to the generation of an immunosuppressive TME, and the crosstalk between macrophages and various immune cells and cytokines in the TME plays an irreplaceable role.

Understanding the main mechanisms by which macrophages participate in tumor immune escape and related targeted therapies will help us improve clinical protocols and develop potential new strategies to overcome macrophage-associated immune tolerance.

 

 

 


Signaling pathways regulating macrophage phagocytosis

How do Tumor-associated macrophages ( TAMs ) work in tumor immunotherapy?

 

 

CD47/SIRPα

CD47 is an immunoglobulin widely distributed on the surface of normal cells, which can negatively regulate anti-tumor immunity by inhibiting phagocytosis, and is involved 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, and the N-terminus of its extracellular region can bind to CD47, resulting in an immunoreceptor tyrosine inhibitory motif ( ITIM ) Phosphorylation of tyrosine on the protein releases the “don’t eat me” signal, thereby inhibiting the phagocytosis mediated by macrophages 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 antibodies or targeted inactivation of the CD47 gene significantly inhibited tumor growth. In addition, anti-CD47 treatment can also alter the polarization state of macrophages in the TME, inducing TAMs to switch to an antitumor state.

 

LILRB1/MHCI

Leukocyte immunoglobulin-like receptor B ( LILRB ) is expressed on most immune cells and consists of an extracellular Ig-like domain, a transmembrane domain, and an intracellular domain containing ITIM. It mediates negative regulation of immune cell activation after binding to the main ligand major histocompatibility complex I ( MHCI ).

MHCI is a complex formed by HLA α chain and β2-microglobulin ( β2M ). Certain tumor cells highly express β2M, which can bind to LILRB1 on macrophages to inhibit phagocytosis, resulting in loss of immune surveillance. Therefore, in patients with normal or high expression of MHCI on tumor cells, drugs targeting the MHCI/LILRB1 axis may promote anti-tumor immune responses and exert synergistic effects with drugs targeting the CD47/SIRPα axis.

 

CD24/Siglec-10

CD24, also known as heat-stable antigen, is a highly glycosylated surface protein anchored by glycosylphosphatidylinositol that can interact with sialic acid-binding immunoglobulin-like lectin-10 (Siglec- 10 ) , to reduce innate immune-mediated deleterious inflammation from infection or liver injury.

Tumor cells highly expressed CD24, while TAM highly expressed Siglec-10. After binding to CD24, ITIM of Siglec-10 can recruit and activate the SH2 domain-containing tyrosine phosphatase SHP-1 or SHP-2, thereby blocking the cytoskeleton rearrangement required for macrophage phagocytosis, triggering inhibitory Signal transduction cascade.

“Don’t eat me” signals CD47, β2M, and CD24, all of which involve ITIM-based macrophage signaling, leading to immune selection of macrophage-resistant cancer cell subpopulations, allowing tumor cells to escape macrophage surveillance and clear. Therefore, mastering the mechanism by which tumor cells express anti-phagocytic signals can better predict the therapeutic effect and target therapy.

 

 


Mechanisms of macrophages involved in immune evasion


Macrophages participate in the formation of the suppressive myeloid microenvironment

Various mediators in the TME are involved in regulating the recruitment of MDSCs and monocytes, and polarizing macrophages through different signaling pathways, thereby promoting the formation of an immunosuppressive myeloid microenvironment.

 

How do Tumor-associated macrophages ( TAMs ) work in tumor immunotherapy?

 

Furthermore, crosstalk between macrophages, MDSCs, and dendritic cells further creates an immunosuppressive myeloid microenvironment.

Ovarian cancer cells highly express CD39 and CD73, which help catalyze the conversion of extracellular ATP to adenosine, which can recruit monocytes and induce their differentiation into TAMs that secrete IL-10.

TAMs express CD39 and CD73, which further increase the infiltration of MDSCs and TAMs, thereby forming a self-amplification mechanism that promotes local immune escape.

 

Tumor-associated neutrophils ( TANs ) are also an important component of the immunosuppressive myeloid microenvironment. Like macrophages, neutrophils can be described as two subpopulations, N1 and N2, with N1 exhibiting antitumor activity and N2 thought to promote tumor metastasis.

In a breast cancer model, IL-1β secreted by TAMs induced γδ T cells to release IL-17 to regulate the release of G-CSF and promote the recruitment of neutrophils to stimulate metastasis, suggesting 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 influence Th cells

There is a mutual regulation between macrophages and helper T cells.

Macrophages rely on TGF-β and IL-10 to convert Th1 cells into Th2 cells to reverse the antitumor effects of CD8+ cytotoxic T cells and CD4+ Th1 cells, which is considered 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 generation of M2 macrophages.

Furthermore, Treg phenotype and function play an important role in the immunosuppressive TME.

Recent studies have shown that macrophages can affect Treg proliferation, migration, and function through various pathways.

First, TAMs can secrete IL-23, promote the proliferation of Treg and the expression of IL-10 and TGF-β, and inhibit the killing of tumor cells by CTL; secondly, macrophages overexpress CCL1, which is the ligand of CCR8 expressed on Treg, to Attracts Tregs into the tumor area; similarly, macrophages secrete CCL22 to induce Tregs to migrate into the tumor area of ​​ovarian cancer, suppress T cell immunity and promote tumor growth.

 

Interaction of macrophages with CAFs

CAFs are the most abundant stromal cells in the TME, which can release a large number of cytokines, synthesize and remodel 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 into mesenchymal cells, and increase the reactivity of CAFs, thereby enhancing the invasiveness of cancer cells.

 

Macrophages mediate immune escape through 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 upregulated by TAM-derived TNF-α, and positively correlates with macrophage infiltration in the tumor stroma.

In the 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 upregulate PD-L1 on TAMs through STAT3 pathway, thereby promoting immune evasion of breast cancer.

 

Meanwhile, the PD-1/PD-L1 axis has a profound impact on macrophage function.

Increased expression of PD-1 on TAMs inhibits their phagocytosis and constitutively acts on the mTOR pathway to negatively regulate macrophage proliferation and activation.

Therefore, PD-1/PD-L1 blockade can also directly affect macrophages.

 

PD-1/PD-L1 blockade promotes the pro-inflammatory polarization of macrophages, enhances the activity of effector T cells, and cooperates with other immune checkpoint inhibitors to limit tumor spread.

 

In addition to the PD-1/PD-L1 axis, some experimental results suggest that TAM can also induce immune escape together with other immune checkpoints such as the CTLA/CD86 axis and TIM3/galectin-9 axis , but definitive evidence is still lacking.

 

The interaction of macrophages with these immune checkpoints in immune evasion deserves further study.

 

Macrophages contribute to the formation of immune unresponsive sites

Immune non-response is an important reason for tumor tissue to escape immune surveillance, and macrophages may participate in the immune immunity of tumor tissue through the following mechanisms. First, macrophages can form a physical barrier by accumulating CAFs to the tumor area, CAFs deposit fibrous collagen, hyaluronic acid, fibronectin, and other substances, and secrete lysyl oxidase to stimulate type I collagen cross-linking.

 

Second, similar to tumor cells, induced TAMs can express Fas-L and release active soluble Fas-L, inducing apoptosis of Fas+ lymphocytes, while CAFs can upregulate Fas-L and PD-L2 through MHC-1 antigen cross-presentation, inhibiting CD8+ T cell activity, resulting in a TME lacking lymphocyte infiltration.

 

In addition, hyaluronic acid secreted by tumor cells can bind to TLR4 on the surface of macrophages, induce TAMs to migrate to tumor-associated areas, and inhibit the expression of C/EBPβ through miR935, and 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


Target TAM

More and more evidences show that TAMs contribute to chemotherapy resistance, and TAM-targeted monotherapy or combination chemotherapy treatments are being tested in preclinical and clinical trials.

 

TAMs are recruited into the TME by CSF-1 to promote breast cancer development and metastasis. Therefore, therapeutic approaches targeting the CSF-1/CSF-1R axis with monoclonal antibodies or small molecule compounds are being tested. RG7155 , a monoclonal antibody targeting CSF-1R, treated 7 patients diagnosed with diffuse giant cell tumor in a phase 1 clinical trial ( NCT01494688 ), all patients experienced PR and 2 patients cr. Furthermore, the number of CD68+CD163+ macrophages was reduced in tumor biopsies of RG7155-treated patients, suggesting a reduction in the recruitment of TAMs to the TME.

 

PLX3397, a tyrosine kinase inhibitor targeting CSF-1R, c-Kit, and Flt3, blocks tumor progression by depolarizing the M2 phenotype of TAMs. PLX3397 is in clinical trials including patients with 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 patients with various solid tumors.

 

In addition to monotherapy, inhibitors targeting CSF-1 or CSF-1R were also tested in combination with chemotherapy. For example, PLX3397 in combination with paclitaxel in patients with advanced solid tumors ( NCT01525602 ); a trial of PLX3397 in combination with eribulin in breast cancer patients ( NCT01596751 ); PLX3397 in combination with vemurafenib in patients with BRAF-mutated melanoma ( NCT01826448 ); PLX3397 in combination with sirolimus for Patients with advanced sarcoma ( NCT02584647 ) et al.

 

In addition, combinations of TAM-targeting agents and immune checkpoint inhibitors are also under development. A clinical trial of IMC-CS4 in combination with durvalumab or tremelimumab in 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 combination trial of ARRY-382 with pembrolizumab ( NCT02880371 ), a combination of BLZ945 with PDR001 ( a monoclonal antibody against PD-1 ) trial ( NCT02829723 ), a trial of RG7155 in combination with atezolizumab ( NCT02323191 ), and a trial of AMG820 in combination with pembrolizumab ( NCT02713529 ).

 

CAR-macrophage

Until November 2020, two clinical trials based on the CAR-M strategy have been approved by the FDA. The first is drug candidate CT-0508 from CARISMA Therapeutics , which treats patients with relapsed/refractory HER2-overexpressing tumors with an anti-HER2 CAR-M ( Phase I clinical trial ).

The other is Maxyte’s MCY-M11 , which uses mRNA to transfect PBMCs to express mesothelin-targeted CARs ( including CAR-M ) for the treatment of patients with relapsed/refractory ovarian cancer and peritoneal mesothelioma, and is currently recruiting volunteers Conduct phase I clinical trials.

 

 

 


Summary


An increasing number of studies have shown that macrophages play key roles in tumor development, metastasis, immune regulation, tumor angiogenesis, TME remodeling, and cancer therapy response.

Macrophage-targeted therapy is expected to become the next frontier of tumor immunotherapy, and elucidating 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 .

 

 

 

 

references:

1. Next frontier in tumor immunotherapy: macrophage-mediated immune evasion. Biomark Res. 2021; 9: 72.

How do Tumor-associated macrophages ( TAMs ) work in tumor immunotherapy?

(source:internet, reference only)


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