What role do Macrophages play in Tumor Immunotherapy?

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What role do Macrophages play in Tumor Immunotherapy?

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What role do Macrophages play in Tumor Immunotherapy?

Tumor-associated macrophages (TAMs) are integral components of the tumor microenvironment, playing roles in angiogenesis, extracellular matrix remodeling, cancer cell proliferation, metastasis, immune suppression, and resistance to chemotherapy and checkpoint blockade immunotherapy.

Conversely, when appropriately activated, macrophages can mediate phagocytosis and cytotoxicity against cancer cells and engage in effective bidirectional interactions with components of the innate and adaptive immune systems. Therefore, they have emerged as crucial therapeutic targets in cancer treatment.

Macrophage-targeting strategies encompass inhibitors of cytokines and chemokines that promote myeloid cell recruitment and polarization, as well as activators of their anti-tumor and immune-stimulatory functions.

Furthermore, early clinical trials suggest that immunotherapies targeting myeloid cell functions have significant anti-tumor potential.

Finally, macrophages are excellent candidates for cell-based therapies, with chimeric antigen receptor macrophages (CAR-Ms) entering clinical evaluation. Targeting macrophages holds promise as the next frontier in tumor immunotherapy.

TAM Plasticity

Macrophages are highly plastic cells capable of different functional activations in response to various signals. They are classified into two forms, M1 and M2. M1 macrophages are induced by bacterial products and interferons in Type 1 immune responses, driven by Th1 helper T cells and innate lymphocytes. In contrast, M2 macrophages are induced by cytokines such as IL-4 and IL-13 in Type 2 immune responses, driven by Th2 helper T cells and innate lymphocytes. M1 polarization is associated with macrophage-dependent tissue damage and tumor cell killing, whereas M2 polarization promotes tissue repair, remodeling, and resistance against parasites.

In the context of cancer, the coordination of this plasticity varies significantly between different tumors or within different regions and stages of the same tumor, resulting in diverse TAM phenotypes. Factors such as tumor-derived cytokines like IL-10 and colony-stimulating factor 1 (CSF1), as well as chemokines like CCL2, CCL18, CCL17, and CXCL4, play pivotal roles in modulating TAM plasticity in the tumor context. A newly emerging factor influencing macrophage polarization is the neurotransmitter gamma-aminobutyric acid (GABA), secreted by activated B lymphocytes. GABA can promote the differentiation of monocytes into anti-inflammatory macrophages that produce IL-10 and inhibit cytotoxic CD8+ T cells. Overall, single-cell analysis of TAMs in mouse and human tumors reveals a complex landscape of macrophages that goes beyond a simple M1/M2 classification.

The Role of Macrophages in Cancer

Studies in mouse models have shown that macrophages are essential components in the dissemination and metastasis of cancer, influencing all stages of this multistep process by interacting with cancer cells, the extracellular matrix, and other components of the innate and adaptive immune systems. For example, in a mouse model of breast cancer, macrophages were found to provide a niche for metastatic spread to the lungs by promoting angiogenesis. In the same model, macrophages also participated in promoting bone metastasis, where IL-4 receptor (IL-4R)-driven M2 polarization was found to be crucial for macrophage-mediated promotion of bone metastasis.

The lymphatic system serves as a major route for the spread of many tumors. In a transplanted breast cancer model, a subgroup of TAMs expressing podoplanin, a glomerular podocyte membrane mucoprotein, mediated extracellular matrix remodeling, lymphangiogenesis, and lymphatic invasion. Macrophages in the subcapsular sinus of lymph nodes provided anchorage for cancer cell dissemination and promoted their growth in a melanoma mouse model.

In human tumors, macrophage infiltration in primary solid tumors and lymphomas is often associated with poor prognosis.

Macrophage Checkpoints and Immune Regulators

CD47/SIRPα

CD47, a widely distributed immunoglobulin on the surface of normal cells, acts as a negative regulator of anti-tumor immunity by inhibiting phagocytosis and participating in cell proliferation, migration, apoptosis, and immune homeostasis. Its main ligand, signal regulatory protein alpha (SIRPα), is a transmembrane protein highly expressed on myeloid cells’ membranes. The N-terminal extracellular region of SIRPα can bind to CD47, leading to tyrosine phosphorylation on immunoreceptor tyrosine-based inhibition motifs (ITIMs), releasing a “don’t eat me” signal that inhibits macrophage-mediated phagocytosis, protecting normal cells from immune destruction.

Research indicates that CD47 is highly expressed in various tumors, such as hematologic malignancies and hepatocellular carcinoma (HCC), and correlates with poor prognosis. Administration of CD47-blocking antibodies or targeting CD47 through genetic silencing can significantly inhibit tumor growth. Moreover, anti-CD47 therapy can also alter the polarization state of macrophages in the tumor microenvironment, inducing TAMs to shift toward an anti-tumor state.

LILRB1/MHCI

Leukocyte immunoglobulin-like receptor B (LILRB) is expressed on most immune cells and contains extracellular Ig-like domains, a transmembrane region, and an intracellular region containing immunoreceptor tyrosine-based inhibition motifs (ITIMs). It mediates negative regulation of immune cell activation upon binding to its primary ligand, major histocompatibility complex I (MHCI).

MHCI is composed of HLAα chains and β2-microglobulin (β2M), and some tumor cells upregulate β2M, allowing it to bind to LILRB1 on macrophages to suppress phagocytosis, leading to immune escape. Therefore, drugs targeting the MHCI/LILRB1 axis may promote anti-tumor immune responses in patients with normal or high MHCI expression on tumor cells, potentially synergizing 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, and it interacts with sialic acid-binding immunoglobulin-like lectin-10 (Siglec-10) to mitigate innate immune-mediated harmful inflammation resulting from infection or liver injury.

Tumor cells often overexpress CD24, while TAMs upregulate Siglec-10. Upon binding to CD24, Siglec-10’s ITIM can recruit and activate tyrosine phosphatases containing SH2 domains, inhibiting the necessary cytoskeletal rearrangement for macrophage phagocytosis and triggering inhibitory signaling cascades.

Efferocytosis Receptors

Several types of efferocytosis receptors are highly expressed in TAMs, and they are emerging as targets for enhancing pro-inflammatory switches.

Clinical evidence suggests a significant correlation between CD163-expressing macrophages and tumor progression in various cancers. CD163 facilitates the clearance of damaged red blood cells by macrophages through binding to hemoglobin-haptoglobin complexes. The exact mechanisms underlying its pro-tumor function remain unclear. However, studies using gene-based and nanoparticle approaches have shown that the elimination of CD163+ macrophages leads

to tumor regression in a melanoma mouse model treated with anti-PD-1 therapy. Other efferocytosis receptors include macrophage mannose receptor (MRC1, also known as CD206), macrophage receptor with collagenous structure (MARCO), and receptor CLEVER-1.

PD1

The expression of PD-1 on TAMs suppresses phagocytosis and anti-tumor immunity, allowing cancer cells expressing PD-L1 to evade both T cell cytotoxicity and macrophage-mediated phagocytosis. This indicates that blockade of this axis may release anti-tumor immunity through adaptive and innate mechanisms. The exact phagocytosis inhibitory mechanisms triggered by PD-1 on macrophages are not yet fully understood, but both SIRPα, LILRB1, and PD-1 contain ITIM domains, which may contribute to downstream signaling inhibition of phagocytosis.

TREM2

Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by macrophages in various tissues and is upregulated on TAMs in human and mouse tumors. Targeting TREM2-expressing macrophages can restrict tumor growth and sensitize responses to anti-PD-1 therapy. PY314, a humanized monoclonal antibody targeting TREM2-expressing macrophages, is currently undergoing Phase I clinical trial evaluation in patients with advanced solid tumors (NCT04691375).

PSGL1

P-selectin glycoprotein ligand-1 (PSGL1) is widely expressed in hematopoietic cells and strongly upregulated by M2 polarization signals in macrophages, resulting in high expression levels in TAMs. Its ligands include VISTA and selectins. Anti-PSGL1 antibodies can repolarize human M2 macrophages toward an M1-like phenotype and exhibit anti-tumor activity in humanized mouse models. Therefore, PSGL1 represents a valuable target for TAM reprogramming.

Clinical Progress of Macrophage Immunotherapy

Targeting TAMs

Increasing evidence suggests that TAMs contribute to chemotherapy resistance, and therapeutic approaches targeting TAMs as monotherapy or in combination with chemotherapy are being tested in preclinical and clinical settings.

TAMs are recruited to the tumor microenvironment (TME) by CSF-1 and promote breast cancer development and metastasis. Thus, therapies targeting the CSF-1/CSF-1R axis with monoclonal antibodies or small molecules are under investigation. RG7155, a monoclonal antibody targeting CSF-1R, was used to treat seven patients with diffuse giant cell tumor in a Phase I clinical trial (NCT01494688). All patients showed partial responses, and two patients achieved complete responses. Additionally, tumor biopsies from patients treated with RG7155 showed reduced numbers of CD68+CD163+ macrophages, indicating reduced recruitment of TAMs to the TME.

Tyrosine kinase inhibitors targeting CSF-1R, c-Kit, and Flt3, such as PLX3397, block tumor progression by depolarizing TAMs from the M2 phenotype. PLX3397 is being tested in clinical trials for various tumors, 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 targeting CSF-1 or CSF-1R are being tested in combination with chemotherapy. For example, PLX3397 is combined with paclitaxel in late-stage solid tumor patients (NCT01525602), PLX3397 is combined with eribulin in breast cancer patients (NCT01596751), PLX3397 is combined with vemurafenib in BRAF-mutant melanoma patients (NCT01826448), and PLX3397 is combined with sirolimus in advanced sarcoma patients (NCT02584647), among others.

Furthermore, the combined use of TAM-targeting agents and immune checkpoint inhibitors (ICIs) is under development. IMC-CS4 is combined with durvalumab or tremelimumab in clinical trials for solid tumor patients (NCT02718911). There are also trials combining PLX3397 with pembrolizumab in various tumor patients (Phase I, NCT02452424), ARRY-382 with pembrolizumab (NCT02880371), BLZ945 with PDR001 (an anti-PD-1 monoclonal antibody, NCT02829723), RG7155 with atezolizumab (NCT02323191), and AMG820 with pembrolizumab (NCT02713529).

CAR-Macrophages (CAR-M)

As of November 2020, two clinical trials based on CAR-M strategies have received FDA approval. The first one is CT-0508, a candidate drug from CARISMA Therapeutics, which utilizes CAR-M targeting HER2 to treat patients with recurrent/refractory HER2-overexpressing tumors in a Phase I clinical trial. The other is MCY-M11 from Maxyte, which employs mRNA-transfected PBMCs expressing a CAR targeting mesothelin, including CAR-Ms, for the treatment of patients with recurrent/refractory ovarian cancer and peritoneal mesothelioma. MCY-M11 is currently recruiting volunteers for a Phase I clinical trial.

Conclusion

Macrophages are common constituents of the tumor microenvironment and engage in complex interactions with cancer cells, stroma, and immune-active cells.

From chemotherapy to immune checkpoint inhibitor (ICI) immunotherapy, macrophages play a dual role in the effectiveness of current treatment modalities.

In many human tumors, TAMs are the primary drivers of resistance to T cell checkpoint blockade and mediate immune therapy resistance.

Targeting TAMs and CAR-M cell therapies based on macrophages have shown immense therapeutic potential in clinical settings.

In the future, macrophages are poised to become a new focal point in cancer immunotherapy.

What role do Macrophages play in Tumor Immunotherapy?

References:
1. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov.2022 Aug 16 : 1–22.
2. Next frontier in tumor immunotherapy:macrophage-mediated immune evasion. Biomark Res. 2021; 9: 72.

(source:internet, reference only)

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