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Why will Macrophages become a new frontier in tumor immunotherapy?
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Why will Macrophages become a new frontier in tumor immunotherapy?
Tumor-associated macrophages ( TAMs ) are at the heart of immune suppressive cells and cytokine networks and play a crucial role in tumor immune evasion.
Therefore, it is crucial to understand the interactions between macrophages and other immune cells and the factors that enhance existing anticancer treatments.
TAMs are functionally heterogeneous and are divided into two major subpopulations, M1 and M2 macrophages.
M1 macrophages are the first line of defense against microbial infection, and M1 macrophages also maintain a strong antigen-presenting ability and induce a strong Th1 response.
Instead, M2 macrophages play a key role in limiting immune responses, inducing angiogenesis and tissue repair.
Thus, the presence of M2-type TAMs is associated with pro-tumor activity, while the presence of M1-type TAMs is associated with antitumor activity.
In conclusion, TAM is the key to the generation of 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 are involved in tumor immune evasion and related targeted therapies will help us improve clinical protocols and develop potential new strategies to overcome macrophage-related immune tolerance.
Signaling pathways regulating macrophage phagocytosis
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 major ligand, signal regulatory protein alpha ( SIRPα ), is a transmembrane protein that is highly expressed on the myeloid cell membrane, and the N-terminus of its extracellular domain can bind to CD47, resulting in an immunoreceptor tyrosine inhibitory motif ( ITIM ) Phosphorylation of tyrosine on the protein releases a “don’t eat me” signal, thereby inhibiting macrophage-mediated phagocytosis and protecting normal cells from damage by the immune system.
Studies have shown that CD47 is highly expressed in various 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 the transformation of TAM into an antitumor state.
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 ITIM-containing intracellular domain.
It mediates the negative regulation of immune cell activation upon binding to the major ligand major histocompatibility complex I ( MHCI ).
MHCI is a complex formed by HLA α chain and β2-microglobulin ( β2M ), which is highly expressed by some tumor cells, which can bind to LILRB1 on macrophages to inhibit phagocytosis, resulting in loss of immune surveillance.
Therefore, in patients with normal or high MHCI expression on tumor cells, drugs targeting the MHCI/LILRB1 axis may promote antitumor immune responses and synergize with drugs targeting the CD47/SIRPα axis.
CD24, also known as a thermostable antigen, is a highly glycosylated surface protein anchored by glycosylphosphatidylinositol that interacts with sialic acid-binding immunoglobulin-like lectin-10 ( Siglec-10 ) , to reduce innate immune-mediated harmful inflammation caused by infection or liver damage.
Tumor cells highly expressed CD24, while TAMs highly expressed Siglec-10. Upon binding to CD24, the ITIM of Siglec-10 recruits and activates SH2 domain-containing tyrosine phosphatases SHP-1 or SHP-2, thereby blocking cytoskeletal rearrangements required for macrophage phagocytosis, triggering inhibitory Signal transduction cascade.
“Don’t eat me” signals CD47, β2M, and CD24, all of which are involved in ITIM-based macrophage signaling, leading to immune selection of macrophage-resistant cancer cell subsets, allowing tumor cells to evade macrophage surveillance and Clear.
Therefore, understanding the mechanism by which tumor cells express anti-phagocytic signals can better predict the therapeutic effect and targeted therapy.
Mechanisms by which macrophages are involved in immune evasion
Macrophages are involved in the formation of an inhibitory myeloid microenvironment
Various mediators in the TME are involved in regulating the recruitment of MDSCs and monocytes, and polarize macrophages through distinct signaling pathways, thereby promoting the formation of an immunosuppressive myeloid microenvironment.
In addition, crosstalk between macrophages, MDSCs, and dendritic cells further shapes the 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 IL-10-secreting TAMs.
TAMs express CD39 and CD73, which further increases the infiltration of MDSCs and TAMs, thereby forming a self-amplifying 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, N1 exhibits antitumor activity and N2 is 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 G-CSF release and promote neutrophil recruitment 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 evasion is unclear.
Macrophages affect Th cells
Reciprocal regulation exists 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 influence the tumor TME by changing the polarization direction of macrophages. Th1 cells secrete IFN-γ to induce M1 polarization, while Th2 cells 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; Attract Tregs into tumor areas; similarly, macrophages secrete CCL22 to induce Tregs to migrate to tumor areas of ovarian cancer, suppress T-cell immunity and promote tumor growth.
Interaction of macrophages with CAF
CAFs are the most abundant stromal cells in the TME, which can release a large number of cytokines, synthesize and remodel the extracellular matrix, and form a tumor-promoting fibrous microenvironment. CAFs secrete IL-6, M-CSF, MCP-1, and stromal cell-derived factor-1 to promote macrophage infiltration and differentiation.
M2, on the other hand, secretes TGF-β to promote endothelial-to-mesenchymal transition and increase CAF reactivity, thereby enhancing cancer cell invasiveness.
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 various tumor tissues, can be upregulated by TAM-derived TNF-α, and positively correlates with macrophage infiltration in tumor stroma.
In the TME, PD-L1 expression 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 via the STAT3 pathway, thereby promoting immune evasion in breast cancer.
Meanwhile, the PD-1/PD-L1 axis has profound effects on macrophage function. Increased PD-1 expression on TAMs inhibits their phagocytosis and structurally acts on the mTOR pathway, negatively regulating macrophage proliferation and activation. Therefore, PD-1/PD-L1 blockade can also directly affect macrophages.
PD-1/PD-L1 blockade promotes pro-inflammatory polarization of macrophages, enhances effector T cell activity, 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 TAMs can also induce immune escape together with other immune checkpoints, such as the CTLA/CD86 axis and the TIM3/galectin-9 axis , but definitive evidence is still lacking. The interaction of macrophages with these immune checkpoints in immune escape deserves further study.
Macrophages contribute to the formation of immune unresponsive sites
Immune unresponsiveness is an important reason for tumor tissues to evade immune surveillance, and macrophages may participate in the immune immunity of tumor tissues through the following mechanisms.
First, macrophages can form a physical barrier by accumulating CAFs to the tumor area, which deposit fibrillar 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 the The activity of CD8+ T cells, thereby forming a TME lacking lymphocytic 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 regions, and inhibit the expression of C/EBPβ through miR935 to promote the differentiation of macrophages to the M2 phenotype, thereby promoting Malignant cells evade immune surveillance and “cool” the immune response.
Clinical progress of macrophage immunotherapy
There is growing evidence that TAMs contribute to chemotherapy resistance, and TAM-targeted monotherapy or combination chemotherapy treatments are being tested in preclinical and clinical settings.
TAMs are recruited to the TME by CSF-1 and 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, was treated in a Phase 1 clinical trial ( NCT01494688 ) in 7 patients diagnosed with diffuse giant cell tumor, with PR in all patients and 2 patients cr.
In addition, the number of CD68+CD163+ macrophages was reduced in tumor biopsies from RG7155-treated patients, indicating decreased TAM recruitment to the TME.
The tyrosine kinase inhibitor PLX3397 targeting CSF-1R, c-Kit and Flt3 blocks tumor progression by depolarizing the M2 phenotype of TAMs. 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 patients with various solid tumors.
In addition to monotherapy, inhibitors targeting CSF-1 or CSF-1R are also being tested in combination with chemotherapy.
For example, PLX3397 in combination with paclitaxel in patients with advanced solid tumors ( NCT01525602 ); PLX3397 in combination with eribulin in a trial in breast cancer patients ( NCT01596751 ); PLX3397 in combination with vemurafenib in patients with BRAF-mutant melanoma ( NCT01826448 ); PLX3397 in combination with sirolimus Patients with advanced sarcoma ( NCT02584647 ) et al.
In addition, a combination of TAM targeting agents and immune checkpoint inhibitors is also under development. A clinical trial of IMC-CS4 in combination with durvalumab or tremelimumab in patients with solid tumors is ongoing ( NCT02718911 ).
There are also Phase 1 trials of PLX3397 in combination with pembrolizumab in patients with various tumors ( NCT02452424 ), ARRY-382 in combination with pembrolizumab ( NCT02880371 ), and BLZ945 in combination with PDR001, a monoclonal antibody against PD-1 trial ( NCT02829723 ), a combination trial of RG7155 with atezolizumab ( NCT02323191 ), and a combination trial of AMG820 with pembrolizumab ( NCT02713529 ).
As of November 2020, two clinical trials based on CAR-M strategies have been approved by the FDA. The first is the 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 transfected PBMCs to express CARs targeting mesothelin ( including CAR-M ) for the treatment of patients with relapsed/refractory ovarian cancer and peritoneal mesothelioma, and is currently recruiting volunteers Phase I clinical trials are being conducted.
An increasing number of 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, and elucidating its interaction mode will help to develop 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.
Why will Macrophages become a new frontier in tumor immunotherapy?
(source:internet, reference only)