4-1BB: Energizing Immune Cells to Overcome Tumor Resistance

Immunotherapy has become a central pillar in the fight against cancer, with a focus on enhancing the body’s natural defenses. Among the molecules at the forefront of immunotherapeutic research is 4-1BB (CD137), a co-stimulatory receptor that plays a key role in amplifying immune cell responses. Agonists like 1D8 target 4-1BB, unleashing potent anti-tumor immunity. This article delves into the function of 4-1BB, how agonists enhance immune responses, and their potential in https://www.assaygenie.com/blog/targetting-immune-checkpoints-as-cancer-therapy

4-1BB, also known as CD137, is a co-stimulatory molecule in the tumor necrosis factor receptor (TNFR) family. Expressed on activated T cells, NK cells, and dendritic cells, it is critical for the proliferation, survival, and enhanced function of immune cells. Unlike some immune receptors that are continuously expressed, 4-1BB is inducible, meaning it only appears when immune cells are activated in response to an infection or malignancy.

When 4-1BB binds to its ligand, 4-1BBL, it activates several downstream signaling pathways that boost immune responses. The engagement of 4-1BB enhances T cell memory, NK cell cytotoxicity, and strengthens the overall anti-tumor response.

When 4-1BB is engaged by its agonists, such as 1D8, it initiates signaling pathways like NF-κB, MAPK, and PI3K-Akt, which are crucial for cell survival and function. This leads to:

• Increased cytokine production (e.g., IL-2, IFN-γ), improving T cell survival and proliferation.


• Improved cytotoxic activity of T cells and NK cells, enabling more effective tumor cell killing.


• T cell memory formation, allowing long-term immune surveillance against cancer.

The therapeutic potential of 4-1BB agonists, such as 1D8, lies in their ability to enhance the immune system’s natural ability to fight cancer. These agonists stimulate CD8+ T cells, natural killer (NK) cells, and dendritic cells, leading to a coordinated attack on tumor cells. The result is enhanced tumor recognition and destruction.

T cells, particularly CD8+ cytotoxic T cells, are central to the immune response against cancer. However, tumors often create an immunosuppressive environment that limits the effectiveness of these T cells. 4-1BB agonists help reverse this by:

• Expanding CD8+ T cells: 4-1BB stimulation increases the number of tumor-specific T cells.


• Promoting T cell memory: Long-term protection against tumor recurrence is achieved by generating memory T cells.


• Enhancing T cell survival: By activating pro-survival pathways, 4-1BB agonists ensure that T cells can persist in the hostile tumor microenvironment.

NK cells are part of the innate immune system and are crucial for eliminating tumor cells that evade detection by T cells. 4-1BB agonists enhance the cytotoxic activity of NK cells, allowing them to better target and destroy tumors, particularly those that may be resistant to T cell-based therapies.

Cancer cells often evade immune detection by exploiting immune checkpoint pathways or creating an immunosuppressive microenvironment. 4-1BB agonists counter this by reinvigorating exhausted immune cells, making them more effective at recognizing and eliminating cancer cells.

Among the various 4-1BB agonists, 1D8 is one of the most studied. As a monoclonal antibody, 1D8 specifically binds to the 4-1BB receptor, triggering a cascade of immune-enhancing effects. In preclinical studies, 1D8 has demonstrated potent anti-tumor activity in several cancer models, including melanoma, colorectal cancer, and lung cancer.

Research suggests that combining 4-1BB agonists with other cancer therapies, such as checkpoint inhibitors (e.g., PD-1/PD-L1 or CTLA-4 blockers), may significantly improve therapeutic outcomes. While checkpoint inhibitors help unblock immune cells, 4-1BB agonists provide the necessary signal to further activate and sustain these cells, leading to a more robust anti-tumor response.

Several clinical trials are underway to test the safety and efficacy of 4-1BB agonists in cancer patients. These trials are exploring the use of 4-1BB agonists in combination with other immunotherapies, including checkpoint inhibitors and cancer vaccines.

While 4-1BB agonists show promise, there are several challenges that need to be addressed to optimize their use in cancer treatment:

• Managing Toxicity: Overstimulation of the immune system by 4-1BB agonists can lead to inflammation and damage to healthy tissues. Researchers are working to develop strategies to minimize these side effects while preserving therapeutic efficacy.


• Optimizing Combinations: Identifying the best therapeutic combinations (e.g.,with checkpoint inhibitors, chemotherapy, or targeted therapies) is critical to improving patient outcomes.

The future of 4-1BB agonists looks promising, particularly in the context of combination immunotherapies. Ongoing research aims to better understand how to integrate 4-1BB agonists into standard cancer treatments, with the goal of maximizing anti-tumor efficacy while minimizing side effects.

4-1BB agonists, such as 1D8, offer a powerful means of stimulating the immune system to fight cancer more effectively. By boosting the activity of T cells and NK cells, and overcoming tumor resistance, these agents have the potential to enhance the efficacy of current immunotherapies and provide new hope for cancer patients.

1. Watts, T.H., 2005. TNF/TNFR family members in costimulation of T cell responses. Annual Review of Immunology, 23, pp.23-68.


2. Chester, C., et al., 2018. 4-1BB agonism: Adding fuel to the fire of T cell anticancer immunity. Cancer Immunology Research, 6(6), pp.703-710.


3. Melero, I., et al., 2017. 4-1BB agonists: multi-potent enhancers of tumor immunity. Oncoimmunology, 6(1), p.e1251539.


4. Wilcox, R.A., et al., 2004. T-cell costimulatory molecules and immune checkpoints as targets for cancer therapy. Cancer Journal, 10(1), pp.25-31.


5. Palazón, A., et al., 2011. CD137 in anti-tumor immunity: Unleashing T cells and NK cells. Seminars in Immunology, 23(5), pp.303-311.


6. Guo, Z., et al., 2018. 4-1BB agonists in cancer immunotherapy. Cancer Treatment Reviews, 62, pp.3-12.


7. Bartkowiak, T., et al., 2015. Costimulation through 4-1BB and OX40: synergistic enhancement of anti-tumor immunity. Journal of Immunology, 194(2), pp.880-890.


8. Ascierto, P.A., et al., 2010. 4-1BB and immunotherapy: coming of age. Cancer Immunology, Immunotherapy, 59(5), pp.715-721.