OX40L (CD252 or TNFSF4) is a protein in the tumor necrosis factor (TNF) superfamily. It regulates immune responses by acting as a communication signal between immune cells. This communication helps direct and modulate the body’s defense mechanisms.
The OX40L-OX40 Signaling Pathway
OX40L connects with its partner protein OX40 (CD134), forming a crucial signaling pathway. OX40L is found on antigen-presenting cells (APCs), such as dendritic cells, which capture and display fragments of threats. The OX40 receptor is primarily on activated T-cells, the immune system’s soldiers.
When an APC presents a threat, OX40L binding to OX40 on the T-cell delivers a powerful “second signal.” This co-stimulatory signal promotes rapid T-cell multiplication and enhances their survival. It also contributes to the formation of “memory” T-cells, which quickly recognize and respond to future threats.
Targeting OX40L to Fight Cancer
Some cancers evade the immune system, making T-cells ineffective. The OX40L-OX40 signaling pathway is a promising therapeutic target. Therapies, called “agonist” therapies, enhance this signal by mimicking OX40L or activating the OX40 receptor on T-cells. These drugs boost T-cells’ ability to attack cancer cells.
Antibodies that activate the OX40 receptor on tumor-infiltrating T-cells increase T-cell proliferation and survival within the tumor microenvironment. This leads to a more robust anti-tumor immune response, potentially shrinking tumors or preventing their growth. Clinical trials are exploring OX40 agonist antibodies, often in combination with other treatments, to improve patient outcomes and overcome immune suppression in advanced cancers.
Blocking OX40L in Autoimmune and Inflammatory Conditions
In contrast to its role in cancer therapy, the OX40L pathway can be overactive in autoimmune diseases and inflammatory conditions. Here, the immune system mistakenly attacks healthy tissues, causing chronic inflammation. An overactive OX40L-OX40 signal promotes the survival and proliferation of self-reactive T-cells, perpetuating inflammation.
To counteract this, “antagonist” therapies are being developed. These drugs block the interaction between OX40L and OX40, calming overactive T-cells. This reduces the proliferation and survival of pathogenic T-cells, mitigating the excessive immune response. For example, in rheumatoid arthritis or inflammatory bowel disease, blocking this pathway can reduce inflammation and tissue damage. Clinical investigations are underway to evaluate OX40L antagonists, aiming to restore immune balance and alleviate symptoms.
The OX40L-OX40 Signaling Pathway
OX40L (CD252 or TNFSF4) and its receptor OX40 (CD134) constitute a co-stimulatory signaling pathway. This interaction is important for T-cell activation, proliferation, and survival.
OX40L: The Ligand
OX40L is a transmembrane protein primarily expressed on activated antigen-presenting cells (APCs). These include:
Dendritic Cells (DCs): Highly efficient at capturing and presenting antigens to T-cells.
Macrophages: Phagocytic cells that can present antigens and express OX40L.
B Cells: Activated B cells can also express OX40L and act as APCs.
Endothelial Cells and Fibroblasts: Under inflammatory conditions, these non-immune cells can also express OX40L.
OX40L’s expression is induced by inflammatory signals, such as cytokines or pathogen-associated molecular patterns (PAMPs).
OX40: The Receptor
OX40 is a transmembrane glycoprotein in the TNF receptor superfamily. It is predominantly expressed on activated T-cells, particularly CD4+ helper T-cells and CD8+ cytotoxic T-cells. Resting T-cells do not express OX40. Its expression is rapidly upregulated following T-cell receptor (TCR) engagement with an antigen and initial co-stimulatory signals.
The Co-stimulatory Signal
The binding of OX40L on an APC to OX40 on an activated T-cell provides a powerful “second signal” for T-cell activation. This signal is distinct from the primary signal delivered through the T-cell receptor (TCR). While TCR engagement and primary co-stimulation initiate T-cell activation, the OX40-OX40L interaction is a “late co-stimulatory” signal that fine-tunes and amplifies the immune response.
Downstream Signaling and Effects on T-cells
Upon binding of OX40L, OX40 initiates a signaling cascade that activates the NF-κB and Akt pathways. Effects on T-cells include:
Enhanced Proliferation: OX40 signaling promotes sustained T-cell proliferation.
Improved Survival: It provides anti-apoptotic signals, increasing the lifespan of activated T-cells.
Cytokine Production: OX40 engagement enhances the production of various cytokines, such as IL-2, IL-4, IL-5, IL-13, and IFN-γ.
Differentiation and Effector Function: It promotes the differentiation of T-cells into effective effector cells.
Memory T-cell Formation: OX40 signaling is involved in the generation and maintenance of long-lived memory T-cells.
The OX40L-OX40 pathway amplifies T-cell responses, ensuring robust immunity against pathogens and tumors. Its dysregulation can contribute to autoimmune diseases and chronic inflammation.
The OX40L-OX40 Signaling Pathway
OX40L (CD252 or TNFSF4) and its receptor OX40 (CD134) constitute a co-stimulatory signaling pathway. This interaction is important for T-cell activation, proliferation, and survival.
OX40L: The Ligand
OX40L is a transmembrane protein primarily expressed on activated antigen-presenting cells (APCs). These include:
Dendritic Cells (DCs): Highly efficient at capturing and presenting antigens to T-cells.
Macrophages: Phagocytic cells that can present antigens and express OX40L.
B Cells: Activated B cells can also express OX40L and act as APCs.
Endothelial Cells and Fibroblasts: Under inflammatory conditions, these non-immune cells can also express OX40L.
OX40L’s expression is induced by inflammatory signals, such as cytokines or pathogen-associated molecular patterns (PAMPs).
OX40: The Receptor
OX40 is a transmembrane glycoprotein in the TNF receptor superfamily. It is predominantly expressed on activated T-cells, particularly CD4+ helper T-cells and CD8+ cytotoxic T-cells. Resting T-cells do not express OX40. Its expression is rapidly upregulated following T-cell receptor (TCR) engagement with an antigen and initial co-stimulatory signals.
The Co-stimulatory Signal
The binding of OX40L on an APC to OX40 on an activated T-cell provides a powerful “second signal” for T-cell activation. This signal is distinct from the primary signal delivered through the T-cell receptor (TCR). While TCR engagement and primary co-stimulation initiate T-cell activation, the OX40-OX40L interaction is a “late co-stimulatory” signal that fine-tunes and amplifies the immune response.
Downstream Signaling and Effects on T-cells
Upon binding of OX40L, OX40 initiates a signaling cascade that activates the NF-κB and Akt pathways. Effects on T-cells include:
Enhanced Proliferation: OX40 signaling promotes sustained T-cell proliferation.
Improved Survival: It provides anti-apoptotic signals, increasing the lifespan of activated T-cells.
Cytokine Production: OX40 engagement enhances the production of various cytokines, such as IL-2, IL-4, IL-5, IL-13, and IFN-γ.
Differentiation and Effector Function: It promotes the differentiation of T-cells into effective effector cells.
Memory T-cell Formation: OX40 signaling is involved in the generation and maintenance of long-lived memory T-cells.
The OX40L-OX40 pathway amplifies T-cell responses, ensuring robust immunity against pathogens and tumors. Its dysregulation can contribute to autoimmune diseases and chronic inflammation.
Targeting OX40/OX40L in Cancer Immunotherapy
The OX40/OX40L pathway is a target for cancer immunotherapy, enhancing anti-tumor T-cell responses. Tumors often create an immunosuppressive microenvironment that inhibits T-cell activity. Therapies activating the OX40 pathway aim to overcome this suppression and boost the immune system’s ability to fight cancer.
OX40 Agonists
The primary strategy in cancer immunotherapy involves OX40 agonists. These agents, typically monoclonal antibodies, bind to and activate the OX40 receptor on T-cells. By mimicking OX40L’s natural binding, these agonists deliver a co-stimulatory signal that enhances T-cell function.
Mechanism of Action
OX40 agonists enhance T-cell function through:
Enhanced T-cell Proliferation and Survival: They promote sustained proliferation of tumor-specific T-cells and protect them from apoptosis. This increases effective anti-tumor T-cells within the tumor microenvironment.
Improved Effector Function: They enhance T-cells’ ability to produce pro-inflammatory cytokines (e.g., IFN-γ, TNF-α) and cytotoxic molecules (e.g., perforin, granzymes), essential for killing cancer cells.
Overcoming Immunosuppression: OX40 activation can reverse T-cell exhaustion and anergy, making T-cells more responsive to tumor antigens.
Promotion of Memory T-cell Formation: They contribute to the generation of long-lived memory T-cells, providing sustained protection against recurrence.
Modulation of Regulatory T-cells (Tregs): Some studies suggest OX40 agonists can reduce the suppressive function of Tregs or even deplete them in the tumor.
Clinical Development
Several OX40 agonist antibodies are in various stages of clinical trials for a range of cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma, and head and neck squamous cell carcinoma. These agents are often investigated as monotherapies or, more commonly, in combination with other immunotherapies (e.g., PD-1/PD-L1 inhibitors, CTLA-4 inhibitors) or conventional treatments (e.g., chemotherapy, radiation). The rationale for combination therapy is to achieve synergistic effects by simultaneously targeting multiple pathways involved in anti-tumor immunity.
Examples of OX40 Agonists in Development include MoAb OX40 (MEDI6469), PF-04518600, and INCAGN01949. These agents aim to provide a potent boost to the immune system, transforming “cold” tumors (those with low immune cell infiltration) into “hot” tumors (those with significant immune cell presence) that are more susceptible to immune attack.
Targeting OX40/OX40L in Cancer Immunotherapy
The OX40/OX40L pathway is a target for cancer immunotherapy, enhancing anti-tumor T-cell responses. Tumors often create an immunosuppressive microenvironment that inhibits T-cell activity. Therapies activating the OX40 pathway aim to overcome this suppression and boost the immune system’s ability to fight cancer.
OX40 Agonists
The primary strategy in cancer immunotherapy involves OX40 agonists. These agents, typically monoclonal antibodies, bind to and activate the OX40 receptor on T-cells. By mimicking OX40L’s natural binding, these agonists deliver a co-stimulatory signal that enhances T-cell function.
Mechanism of Action
OX40 agonists enhance T-cell function through:
Enhanced T-cell Proliferation and Survival: They promote sustained proliferation of tumor-specific T-cells and protect them from apoptosis. This increases effective anti-tumor T-cells within the tumor microenvironment.
Improved Effector Function: They enhance T-cells’ ability to produce pro-inflammatory cytokines (e.g., IFN-γ, TNF-α) and cytotoxic molecules (e.g., perforin, granzymes), essential for killing cancer cells.
Overcoming Immunosuppression: OX40 activation can reverse T-cell exhaustion and anergy, making T-cells more responsive to tumor antigens.
Promotion of Memory T-cell Formation: They contribute to the generation of long-lived memory T-cells, providing sustained protection against recurrence.
Modulation of Regulatory T-cells (Tregs): Some studies suggest OX40 agonists can reduce the suppressive function of Tregs or even deplete them in the tumor.
Clinical Development
Several OX40 agonist antibodies are in various stages of clinical trials for a range of cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma, and head and neck squamous cell carcinoma. These agents are often investigated as monotherapies or, more commonly, in combination with other immunotherapies (e.g., PD-1/PD-L1 inhibitors, CTLA-4 inhibitors) or conventional treatments (e.g., chemotherapy, radiation). The rationale for combination therapy is to achieve synergistic effects by simultaneously targeting multiple pathways involved in anti-tumor immunity.
Examples of OX40 Agonists in Development include MoAb OX40 (MEDI6469), PF-04518600, and INCAGN01949. These agents aim to provide a potent boost to the immune system, transforming “cold” tumors (those with low immune cell infiltration) into “hot” tumors (those with significant immune cell presence) that are more susceptible to immune attack.
Targeting OX40/OX40L in Autoimmune and Inflammatory Diseases
The OX40/OX40L pathway plays a role in various autoimmune and chronic inflammatory diseases. Uncontrolled T-cell responses contribute to tissue damage and disease progression. Inhibiting the OX40/OX40L interaction is a therapeutic strategy to dampen aberrant immune activity.
Role in Autoimmunity and Inflammation
In autoimmune diseases, self-reactive T-cells are inappropriately activated and maintained, leading to an attack on the body’s own tissues. The OX40/OX40L co-stimulation pathway contributes to this by:
Promoting Survival of Pathogenic T-cells: OX40 signaling enhances the survival of effector T-cells, allowing them to accumulate and mediate sustained tissue destruction.
Enhancing Proliferation: It drives the proliferation of activated T-cells, expanding the pool of inflammatory cells.
Sustaining Cytokine Production: OX40 engagement promotes the production of pro-inflammatory cytokines (e.g., IFN-γ, IL-17, TNF-α) by T-cells.
Facilitating T-cell Migration: In some contexts, OX40 signaling can influence the migration of T-cells to inflammatory sites.
Modulating Regulatory T-cells (Tregs): In inflammatory settings, it often supports effector T-cell responses over regulatory ones.
Conditions where the OX40/OX40L pathway is implicated include:
Rheumatoid Arthritis (RA): Increased expression of OX40 and OX40L is found in the synovial fluid and tissue of RA patients, contributing to joint inflammation and destruction.
Systemic Lupus Erythematosus (SLE): Elevated OX40L expression on B cells and APCs, and OX40 on T-cells, correlates with disease activity.
Inflammatory Bowel Disease (IBD) (Crohn’s disease and ulcerative colitis): The pathway contributes to chronic gut inflammation.
Multiple Sclerosis (MS): OX40/OX40L signaling promotes the survival and pathogenic function of autoreactive T-cells in the central nervous system.
Asthma and Allergic Diseases: OX40L expressed on APCs can promote Th2 responses, which are involved in allergic inflammation.
Graft-versus-Host Disease (GVHD): This pathway is involved in the activation and expansion of donor T-cells that attack host tissues after allogeneic hematopoietic stem cell transplantation.
OX40/OX40L Antagonists
Therapeutic strategies focus on blocking this interaction using antagonists. These agents aim to reduce the number and activity of pathogenic T-cells, thereby suppressing inflammation and preventing tissue damage.
Mechanism of Action
Antagonists reduce T-cell activity through:
Inhibition of T-cell Proliferation: By blocking the co-stimulatory signal, antagonists can limit the expansion of activated, self-reactive T-cells.
Promotion of T-cell Apoptosis: They can reduce the survival signals to activated T-cells, leading to their programmed cell death.
Reduction of Pro-inflammatory Cytokine Production: Antagonists can suppress the production of cytokines that drive inflammation.
Modulation of Effector Functions: They can reduce the overall effector functions of pathogenic T-cells.
Clinical Development
Several OX40/OX40L antagonists, primarily monoclonal antibodies, are under investigation for various autoimmune and inflammatory conditions. These include MEDI0562 (an anti-OX40L antibody) and KHK4083 (AMG557), an anti-OX40 antibody. These agents aim to provide a targeted approach to immunosuppression, reducing the systemic side effects often associated with broader immunosuppressive therapies. The goal is to restore immune homeostasis by selectively dampening the aberrant T-cell responses that drive disease.
Targeting OX40/OX40L in Autoimmune and Inflammatory Diseases
The OX40/OX40L pathway plays a role in various autoimmune and chronic inflammatory diseases. Uncontrolled T-cell responses contribute to tissue damage and disease progression. Inhibiting the OX40/OX40L interaction is a therapeutic strategy to dampen aberrant immune activity.
Role in Autoimmunity and Inflammation
In autoimmune diseases, self-reactive T-cells are inappropriately activated and maintained, leading to an attack on the body’s own tissues. The OX40/OX40L co-stimulation pathway contributes to this by:
Promoting Survival of Pathogenic T-cells: OX40 signaling enhances the survival of effector T-cells, allowing them to accumulate and mediate sustained tissue destruction.
Enhancing Proliferation: It drives the proliferation of activated T-cells, expanding the pool of inflammatory cells.
Sustaining Cytokine Production: OX40 engagement promotes the production of pro-inflammatory cytokines (e.g., IFN-γ, IL-17, TNF-α) by T-cells.
Facilitating T-cell Migration: In some contexts, OX40 signaling can influence the migration of T-cells to inflammatory sites.
Modulating Regulatory T-cells (Tregs): In inflammatory settings, it often supports effector T-cell responses over regulatory ones.
Conditions where the OX40/OX40L pathway is implicated include:
Rheumatoid Arthritis (RA): Increased expression of OX40 and OX40L is found in the synovial fluid and tissue of RA patients, contributing to joint inflammation and destruction.
Systemic Lupus Erythematosus (SLE): Elevated OX40L expression on B cells and APCs, and OX40 on T-cells, correlates with disease activity.
Inflammatory Bowel Disease (IBD) (Crohn’s disease and ulcerative colitis): The pathway contributes to chronic gut inflammation.
Multiple Sclerosis (MS): OX40/OX40L signaling promotes the survival and pathogenic function of autoreactive T-cells in the central nervous system.
Asthma and Allergic Diseases: OX40L expressed on APCs can promote Th2 responses, which are involved in allergic inflammation.
Graft-versus-Host Disease (GVHD): This pathway is involved in the activation and expansion of donor T-cells that attack host tissues after allogeneic hematopoietic stem cell transplantation.
OX40/OX40L Antagonists
Therapeutic strategies focus on blocking this interaction using antagonists. These agents aim to reduce the number and activity of pathogenic T-cells, thereby suppressing inflammation and preventing tissue damage.
Mechanism of Action
Antagonists reduce T-cell activity through:
Inhibition of T-cell Proliferation: By blocking the co-stimulatory signal, antagonists can limit the expansion of activated, self-reactive T-cells.
Promotion of T-cell Apoptosis: They can reduce the survival signals to activated T-cells, leading to their programmed cell death.
Reduction of Pro-inflammatory Cytokine Production: Antagonists can suppress the production of cytokines that drive inflammation.
Modulation of Effector Functions: They can reduce the overall effector functions of pathogenic T-cells.
Clinical Development
Several OX40/OX40L antagonists, primarily monoclonal antibodies, are under investigation for various autoimmune and inflammatory conditions. These include MEDI0562 (an anti-OX40L antibody) and KHK4083 (AMG557), an anti-OX40 antibody. These agents aim to provide a targeted approach to immunosuppression, reducing the systemic side effects often associated with broader immunosuppressive therapies. The goal is to restore immune homeostasis by selectively dampening the aberrant T-cell responses that drive disease.