Tumor treatment: Targeting innate immunity

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Tumor treatment: Targeting innate immunity

Tumor treatment: Targeting innate immunity.  Innate immune cells, such as dendritic cells (DCs), use pattern recognition receptors (PRRs) pathogen-related molecular patterns and damage-related molecular patterns (PAMP/DAMPs) to identify pathogens and cancer neoantigens released by ICDs, etc., to discover Early tumors.

These mechanisms trigger the pro-inflammatory program, release pro-inflammatory cytokines, chemokines and type I interferons, and accompany DC cell maturation and migration to lymph nodes, participate in the adaptation of the immune system, and activate and activate antigen-specific T cells. Under the attraction of the chemokine gradient, T cells infiltrate the tumor bed, recognize their homologous antigen, and mediate tumor elimination.

Tumor immune cycle (Document 1)

Other innate immune cells, such as macrophages and natural killer cells, directly kill tumor cells through phagocytosis and cytotoxic mechanisms to eliminate tumors.

Natural immune activating drugs

Toll-like Receptors (TLRs) agonists and antagonists

TLRs are highly conserved transmembrane and intracellular PRRs found in a variety of cell types, and play a key role in the surveillance of microbial pathogens by innate immune cells.

In humans, 10 TLRs have been identified, and they are expressed in T cells, B cells, APCs, and a variety of non-immune cells, including epithelial cells and endothelial cells. TLRs are located in two different areas of the cell: cell membrane and intracellular bodies. TLR1, 2, 5, and 6 are present in the plasma membrane, TLR3, 7, 8, and 9 are expressed in intracellular bodies, and TLR4 is present in both locations.

The dual role of TLRs in tumor immunity

Anti-tumor activity

TLRs are expressed in immune cells and tumor cells in the tumor microenvironment. For example, chemotherapy can cause DMAPs, which can activate TLR4 and so on to lead to DC maturation, activate TLR9 to activate pDC to release type 1 interferon, and activate TLR7/8 to induce polarization of M2 type TAM to anti-tumor M1 type TAM. In addition, TLRs activation can inhibit Treg function, enhance the survival, proliferation and cytokine production of CD8+T.

Promote tumor

• Activation of NF-κB axis up-regulates anti-apoptotic factors (Bcl-XL, Bcl-2, Survivin)
• Moreover, up-regulation of matrix metalloproteinases (MMPs) leads to the degradation of extracellular matrix. The activation of TLR4 can lead to the overexpression of MMP2 and β1-integrin, and the increase of TLR9 increases MMP13 in breast cancer.
• TLR2, TLR4 and TLR9 induce the increase of PG-E2 and COX-2, and TLR4 induces EGFR phosphorylation, which is the most important mechanism in TLRs-mediated angiogenesis.
• Activating TLR can stimulate tumor cells or tumor infiltrating cells to produce suppressor cytokines and chemokines, which not only suppress immune cells, but also attract more suppressive immune cells into the tumor microenvironment (such as MDSC, TAM and CAF) to meet the needs of tumors. demand.
• The downstream signal of TLR can make tumor cells and tumor infiltrating cells convert their metabolic pathways from oxidative phosphorylation to glycolysis.

Three TLR agonists have currently been approved by the FDA and are in clinical use.

1. BCG is an attenuated Mycobacterium bovis, a TLR2/4 ligand, and is approved for the treatment of superficial, non-muscle invasive bladder cancer.
2. The TLR4 agonist monophosphoryl A is approved as a vaccine adjuvant
3. The TLR7 agonist miquimod is approved for the treatment of genital warts and basal cell carcinoma

Some clinical stage TLRs agonists

cGAS/STING

cGAS senses cytoplasmic pathogen DNA or tumor cell DNA, and activates STING (Stimulator of IFN genes) by synthesizing cyclic dinucleotides, cGAMP, and then activates the transcription factors IRF-3 and NF-kB to release type 1 IFN. Related content can click to read: STING: New core of innate immunity, new target of immunotherapy

Synthetic cyclic dinucleotides (CDNs) are the most successful in activating STING because of their structural versatility and ability to bind STING allelic variants.

Most STING is administered by intratumoral injection, but BMS-986301 is being evaluated for systemic intramuscular administration. In addition, GSK3745417 is an intravenous agonist used alone or in combination with ICI to treat advanced solid tumors [NCT03956680, NCT03843359]

RLRs and RIG-I

RLRs (Retinoic Acid Inducible Gene-I-like Receptors) recognize the cytoplasmic RNA produced by viral infections, and the most studied are RIG1, MDA5, and LGP2. RIG1 mediates a wide range of immunostimulatory functions, including DC maturation, T cell activation, and enhancement of NK cell degranulation and cytolytic activity. RIG-I also initiates programmed cell death through internal and external apoptotic pathways, as well as pyrolysis.

Inflammasome

• Inflammasome (Inflammasome) is a multimeric protein complex composed of sensors, adaptors and zymogen Proaspase-1.
• The assembly of inflammasomes is the response of natural immune cells to pathogen-related molecular patterns (PAMP) and damage-related molecular patterns (DAMP).
• Inflammatory bodies cause Caspase-1 to self-cleavage, activate, and then cleave Pro-IL-1β and Pro-IL-18 to form mature IL-1β and IL-18.
• Activated caspase-1 can also cleave GasderminD, leading to a special type of cell death called pyroptosis.
• Inflammasome related content can click to read: Inflammasome (Inflammasome) and targeted drugs

Innate immune cells

DC cells

• DCs are a key component of the anti-tumor response of the natural immune system. There are many strategies for DC cells:
• Strategies for PRRs, such as TLRs and RIG-I agonists, mediate their anti-tumor effects by activating DCs.
• DC cell activation and mobilization agents, such as FLT3 ligand, are being evaluated in clinical trials [NCT03789097]
• Anti-DC cell inhibitory procedures, such as the use of STAT3 and IDO inhibitors.
• The DC vaccine Sipuleucel-T is already on the market.

TAM

Polarizing M2 TAM, which promotes tumor development, to anti-tumor M1 is the main strategy.

Colony Stimulating Factor 1 (CSF-1)

Blocking the binding of macrophages CSF-1 and CSF-1R resulted in the loss of M2 TAM and enrichment of M1 TAM, and the tumors of the mouse preclinical model were controlled. Antibodies and small molecule inhibitors of CSF-1R are undergoing clinical studies of monotherapy and are used in combination with chemotherapy and ICI.

PI3K-γ Inhibition

PI3K is activated by the p110γ subtype in macrophages to drive polarization to M2 TAM. Inhibition of PI3Kγ can promote the polarization of macrophages to M1 TAM, the release of pro-inflammatory factors, and have anti-tumor activity. IPI-549 (Infinity Pharmaceuticals) is undergoing clinical research.

CD47- SIRPa

CD47-SIRPa transmits the don’t eat me signal to macrophages, blocking CD47-SIRPa has become a popular immune development strategy.
For more information, please click to read: CD47 structure, function, biomacromolecule drug development

DC-SIGN

DC-SIGN, also known as CD209, is a marker of immunosuppressive TAMs. The infiltration of DC-SIGN+TAM in clinical specimens is associated with an increase in the proportion of immunosuppressive regulatory T cells and depleted CD8 T cells (TIGITLAG3). The monoclonal antibody against DC-SIGN combined with PD-1 blockade to treat human muscle invasive bladder cancer. Compared with monotherapy, the anti-tumor activity is enhanced, laying the foundation for clinical development.

Other targets include arginase 1, CCL5 and so on.

Anti-tumor development target of macrophages (Reference 1)

NK cells

Although the therapeutic targeting of activating receptors on NK cells has attracted much attention, most methods have not yet been clinically tested.

NKG2D Ligands

The most widely studied activation receptors are NKG2D and its ligands, major histocompatibility complex (MHC) class I chain-associated protein A (MICA) and MHC class I chain-associated protein B (MICB). MICA and MICB are polymorphic proteins induced by cellular stress, injury or transformation, and act as a “kill me” signal by binding to the NKG2D receptor expressed on cytotoxic lymphocytes.

Unfortunately, many cancers shed MICA and MICB through proteolytic cleavage by ADAM10, ADAM17, and MMP14 matrix metalloproteinases. Small molecule inhibitors of metalloproteinases, proteasome inhibitors, etc. are under development.

NK Cell Engagers (NKCEs)

NKCEs such as secondary antibodies and tertiary antibodies to recruit NK cells are under development.

NKG2A inhibitor

NKG2A is an inhibitory checkpoint on NK, and its inhibitor Monalizumab has a good effect in phase III clinical trials of head and neck tumors.

CAR-NK

CAR-NK cells have the potential to be made into spot cell therapy products and are receiving global attention, and a series of clinical trials are underway. Related content can read: NK cell tumor immunotherapy

Expert Comments:

Innate immune cells and molecular pathways are important areas of the body’s anti-tumor immunity. This article briefly sorts out the content in this area.

(source:internet, reference only)

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