Immune checkpoints in cancer pathway

Immune checkpoints are molecules that regulate the immune system’s response to threats. They help maintain balance by preventing excessive immune activation that could harm healthy tissues. In cancer, however, this balance can be disrupted. Tumors often use these checkpoints to avoid being recognized and destroyed by immune cells.

Our immune checkpoints in cancer pathway poster highlights the key checkpoint proteins involved in T cell and Natural Killer (NK) cell regulation, along with their ligands and interactions within the tumor microenvironment.

Download our immune checkpoint pathway

T cells are central in the immune response. They are responsible for identifying and attacking abnormal cells, including cancer cells. Their activity is tightly controlled by checkpoint receptors that either stimulate or suppress their function. Among the most studied is PD-1, or programmed cell death protein 1. When PD-1 binds to its ligands, PD-L1 or PD-L2, it sends inhibitory signals that reduce T cell activity. This interaction is a common target in immunotherapy. Another key molecule is CTLA-4, which competes with CD28 for binding to CD80 and CD86, thus reducing T cell activation. Other receptors, such as LAG-3, TIM-3, and TIGIT, are associated with T cell exhaustion, a state where T cells lose their ability to respond effectively to cancer. On the other hand, co-stimulatory receptors like OX40, ICOS, 4-1BB, and CD28 promote T cell proliferation and survival when activated. The balance between these activating and suppressive signals determines the strength and duration of the immune response.

Natural killer (NK) cells are another important part of the immune system. Unlike T cells, NK cells can recognize and kill cancer cells without prior sensitization. However, they also express checkpoint receptors that modulate their activity. When engaged, molecules such as NKG2A, LIR1, TIGIT, and Siglec-7/9 inhibit NK cell function. Others like CD200R, CD47, and BTLA contribute to tumor immune evasion. Emerging targets such as VISTA and HVEM may also affect NK cell regulation. The poster illustrates how these checkpoints interact with ligands on tumor cells, antigen-presenting cells (APCs), and cancer-associated fibroblasts (CAFs), creating a suppressive microenvironment that hinders immune responses.

Cancer cells do not act alone in suppressing the immune system. They shape their surroundings to create a hostile environment for immune cells. Tumor cells express ligands like PD-L1, PD-L2, and CD47 that engage inhibitory receptors on immune cells. CAFs and APCs release suppressive cytokines such as IL-10, IL-35, and TGF-β, which further suppress the immune response activity. Cytokine receptors found on T cells and NK cells respond to both activating signals, like IL-2 and IL-17, and suppressive ones, like IL-10. Adenosine, produced via CD39 and CD73, is another immunosuppressive molecule that accumulates in the tumor microenvironment and reduces immune cell function.

Understanding immune checkpoints opens new diagnostic and therapeutic strategies for researchers and healthcare professionals. It helps explain why some patients respond well to immunotherapy while others do not, and guides the development of combination treatments that target multiple pathways. Whether working in drug discovery, translational research, or clinical development, immune checkpoint pathways offer a rich area for exploration.

Our poster provides a comprehensive overview of these intricate pathways, highlighting the complexity of immune regulation and the potential for targeted intervention.

References

1. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer 12, 252–264 (2012).
2. Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential.  Cell  161, 205–214 (2015).
3. Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer–immune set point.  Nature  541, 321–330 (2017).
4. Andrews, L. P., Yano, H., Zha, J., & Sharma, P. Immune checkpoint biology and therapy.  Journal of Immunology  200, 2–10 (2018).