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CD155: Breaking Immune Suppression in Tumor Environments

CD155: Breaking Immune Suppression in Tumor Environments

Introduction to CD155 in Cancer Immunotherapy

CD155, also known as Poliovirus Receptor (PVR), is a transmembrane protein that plays a pivotal role in tumor immune evasion. While CD155 is normally involved in cell adhesion and migration, its overexpression on tumor cells creates an immunosuppressive environment by engaging inhibitory receptors on natural killer (NK) cells and T cells. Through these interactions, CD155 contributes to the suppression of the body's natural immune responses, helping tumors evade detection and destruction.


Targeting CD155 has emerged as a promising strategy to break immune suppression in the tumor microenvironment, allowing immune cells to regain their tumor-killing functions. Monoclonal antibodies such as SKII.4 have been developed to block CD155 interactions with inhibitory receptors like TIGIT and CD96, aiming to restore immune activity and enhance anti-tumor responses.


This article explores the biology of CD155, its role in cancer progression, and the potential of CD155-targeting therapies to revolutionize cancer treatment by reinvigorating immune responses in patients with advanced malignancies.


CD155: Structure and Function in Immune Regulation

CD155 and Its Interactions in the Tumor Microenvironment


CD155 is a member of the Nectin-like family of adhesion molecules and is found on both normal and cancerous cells. Under physiological conditions, CD155 is involved in processes like cell adhesion and tissue regeneration. However, in cancer, CD155 is frequently overexpressed on the surface of tumor cells, especially in aggressive cancers such as:


CD155 binds to both activating and inhibitory receptors on immune cells, depending on the context. The critical inhibitory receptor involved in tumor immune evasion is TIGIT (T cell immunoreceptor with Ig and ITIM domains), while activating receptors include DNAM-1 (CD226). When CD155 binds to TIGIT, the immune response is suppressed, effectively inhibiting NK cell and T cell function, and allowing tumor cells to evade immune destruction.


CD155 Receptors: Activating and Inhibitory Pathways

CD155's role in immune suppression is primarily mediated through its interaction with TIGIT. However, CD155 can bind to several receptors with different outcomes, depending on which receptor dominates the interaction. Below is an overview of CD155's interactions:


Receptor

Type

Effect

Inhibitory

Suppresses NK and T cell activity, promotes tumor immune evasion

Inhibitory

Competes with DNAM-1 for CD155 binding, limits NK cell activation

Activating

Promotes NK and T cell activation, enhances anti-tumor responses

In the tumor microenvironment, the overexpression of CD155 and the increased engagement of TIGIT result in immune suppression, tipping the balance away from immune activation and allowing cancer cells to survive and proliferate.


CD155's Role in Tumor Immune Evasion

Suppression of NK and T Cell Activity


CD155 plays a significant role in helping tumors escape immune surveillance by inhibiting the function of cytotoxic NK cells and effector T cells. By interacting with TIGIT, CD155 reduces the ability of these immune cells to proliferate, produce cytokines like IFN-γ, and kill tumor cells. In cancer patients, high levels of CD155 on tumors are often correlated with poor prognosis, due to the diminished immune response.

The interaction between CD155 and TIGIT is particularly important in the development of immune exhaustion, a state where T cells become dysfunctional and unable to effectively combat tumor cells. In tumors with high CD155 expression, immune cells are progressively rendered inactive, creating an immunosuppressive microenvironment that protects the tumor from immune attack.


Impact of CD155 on the Tumor Microenvironment


The tumor microenvironment is often characterized by high CD155 expression and a lack of immune cell infiltration due to the suppressive effects of CD155-TIGIT signaling. In addition to inhibiting immune cells, CD155 can also modulate the behavior of the tumor itself by promoting cell migration, metastasis, and angiogenesis. As such, CD155 serves as both a marker of aggressive cancer behavior and a mediator of immune suppression.


The therapeutic challenge, therefore, is to block CD155 interactions with inhibitory receptors like TIGIT while preserving its interactions with activating receptors like DNAM-1. This approach can restore immune cell function and enhance the body's natural ability to fight cancer.


CD155-Targeted Therapies: Breaking Immune Suppression

SKII.4: A Monoclonal Antibody Targeting CD155


SKII.4 is a monoclonal antibody specifically designed to block the interaction between CD155 and TIGIT, thereby preventing the immunosuppressive signaling that allows tumors to evade destruction. By targeting CD155, SKII.4 aims to:

  • Restore NK cell and T cell function by preventing inhibitory signals from TIGIT.
  • Enhance tumor clearance through the reactivation of cytotoxic immune cells.
  • Improve immune infiltration into the tumor microenvironment, facilitating a more robust anti-tumor response.

By blocking CD155, SKII.4 allows NK cells and T cells to regain their cytotoxic activity, promoting tumor cell lysis and reducing the tumor's ability to escape immune detection.


Mechanism of Action of SKII.4


The mechanism of action of SKII.4 involves its ability to block the CD155-TIGIT interaction without affecting CD155's interaction with DNAM-1, which is essential for activating immune responses. Here's how SKII.4 works:


  1. Inhibition of CD155-TIGIT Binding: SKII.4 binds to CD155, preventing it from interacting with TIGIT, which is the primary receptor responsible for immune suppression in the tumor microenvironment.
  2. Restoration of NK and T Cell Function: By blocking TIGIT engagement, SKII.4 restores the ability of NK cells and T cells to proliferate, produce pro-inflammatory cytokines, and kill tumor cells.
  3. Enhanced Tumor Cell Lysis: With immune suppression lifted, cytotoxic NK cells and T cells can effectively attack and eliminate tumor cells.
  4. Synergy with Other Immunotherapies: SKII.4 can work synergistically with other checkpoint inhibitors like PD-1 or CTLA-4 to produce a more comprehensive anti-tumor immune response.

Clinical Potential of SKII.4 in Cancer Therapy


Preclinical studies and early clinical trials have shown promising results for SKII.4 in treating cancers with high CD155 expression, such as melanoma, lung cancer, and colorectal cancer. By targeting CD155, SKII.4 has the potential to enhance the efficacy of existing immunotherapies and provide a novel treatment option for patients with refractory or relapsed cancers.


Cancer Type

CD155 Expression

Potential of SKII.4

High on tumor cells

SKII.4 can restore NK cell activity and improve tumor clearance

Frequently overexpressed in NSCLC

CD155 blockade can enhance T cell responses, especially in combination with PD-1 inhibitors

High in metastatic cases

SKII.4 can break immune suppression and promote better immune infiltration

The ability of SKII.4 to reinvigorate exhausted immune cells makes it a compelling candidate for combination therapies, particularly in tumors where checkpoint inhibitors alone have been less effective.


Combination Strategies with CD155 Blockade

Synergistic Effects with Checkpoint Inhibitors


Targeting CD155 with SKII.4 can significantly enhance the effects of checkpoint inhibitors like anti-PD-1 and anti-CTLA-4. By addressing multiple immune suppression pathways simultaneously, combination therapies can lead to deeper and more sustained immune responses. For instance:

  • Anti-PD-1 and Anti-TIGIT: Combining SKII.4 with anti-PD-1 therapy has been shown to increase the infiltration of activated T cells into the tumor microenvironment, leading to better overall tumor control.
  • Anti-CTLA-4: Combining CD155 blockade with anti-CTLA-4 may help to reverse immune suppression in the early stages of the immune response, allowing for a more comprehensive anti-tumor attack.


    • CD155 Blockade in Hematologic Malignancies

    While most research on CD155 has focused on solid tumors, there is growing interest in the role of CD155 in hematologic cancers such as acute myeloid leukemia (AML) and non-Hodgkin’s lymphoma. CD155 is often upregulated in these malignancies, contributing to immune suppression and disease progression. SKII.4 has the potential to enhance NK cell activity in these cancers, making it a promising therapeutic candidate for both solid tumors and blood cancers.


    Challenges and Future Directions in CD155-Targeted Therapy

    Managing Immune-Related Toxicities


    As with other immune-modulating therapies, there is a risk of immune-related adverse events (irAEs) with CD155 blockade. These toxicities may include:

    • Cytokine release syndrome (CRS): A hyperactivation of the immune system leading to fever, fatigue, and inflammation.
    • Autoimmune reactions: Unintended attacks on healthy tissues due to overactivation of T cells and NK cells.

    Future clinical trials will focus on optimizing the dosing and timing of CD155-targeted therapies to minimize these risks while maintaining their therapeutic efficacy.


    Overcoming Tumor Resistance


    Some tumors may develop resistance to CD155-targeted therapies by downregulating CD155 or by upregulating alternative immune checkpoint pathways. To counteract this, researchers are exploring combination strategies that target multiple immune checkpoints or engage different immune cells, such as macrophages and dendritic cells, to ensure a more comprehensive anti-tumor response.


    Expanding the Use of CD155 Blockade in Other Cancers


    As research continues to uncover the role of CD155 in different cancer types, there is significant potential for expanding the use of CD155-targeting therapies like SKII.4 beyond solid tumors and into more rare malignancies and metastatic cancers. Biomarker-driven approaches will help to identify the patients who are most likely to benefit from CD155 blockade, ensuring more personalized and effective treatment options.


    Conclusion

    CD155 plays a central role in immune suppression within the tumor microenvironment, contributing to tumor immune evasion and progression. Targeting CD155 with therapies like SKII.4 represents a promising new approach in cancer immunotherapy, offering the potential to restore immune function and enhance tumor destruction. As clinical research progresses, CD155-targeted therapies are poised to become an integral part of combination strategies that could revolutionize the treatment of a wide range of cancers, from melanoma to hematologic malignancies.


    References

  • Johnston, R.J., et al., 2014. The immunoreceptor TIGIT regulates anti-tumor and antiviral CD8+ T cell effector function. Nature, 507(7490), pp.63-69.
  • Yu, X., Harden, K., Gonzalez, L.C., et al., 2009. The surface protein TIGIT suppresses T cell activation. Nature Immunology, 10(1), pp.48-57.
  • Whelan, S., Ophir, E., Kotturi, M.F., et al., 2019. CD155 modulates immune responses in cancer through TIGIT and DNAM-1. Cancer Immunology Research, 7(2), pp.193-203.
  • Chauvin, J.M., Zarour, H.M., 2020. TIGIT in cancer immunotherapy. Journal for ImmunoTherapy of Cancer, 8(2), pp.12-19.
  • Hsu, J., et al., 2018. Enhanced anti-tumor immunity through targeting of CD96 and TIGIT. Journal of Clinical Investigation, 128(3), pp.805-820.
  • Martinet, L., et al., 2019. CD155 expression on human tumors and its role in immune evasion. Journal of Clinical Oncology, 37(15), pp.121-128.
  • Manieri, N.A., Chiang, E.Y., Grogan, J.L., 2017. TIGIT: A key inhibitor of the cancer immunity cycle. Trends in Immunology, 38(1), pp.20-28.
  • Harjunpää, H., Guillerey, C., 2020. TIGIT as an emerging immune checkpoint. Clinical and Translational Immunology, 9(12), pp.e1125.
    • 29th Oct 2024 Zainab Riaz

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