Cancer immunotherapy has emerged as a groundbreaking approach in the fight against cancer by employing the body's own immune system to identify and eliminate tumor cells¹.  Our Cancer immunotherapy poster explores the cancer immunity cycle and all its key elements to understand how they contribute to the effectiveness of cancer immunotherapy.

The cancer-immunity cycle is a series of steps that describe how the immune system detects and eliminates cancer cells. This cycle involves several key stages, which are highlighted in our poster. It starts the release of antigens from cancer cells, which are then captured and processed by antigen-presenting cells, such as dendritic cells. These cancer-associated antigens are presented to T cells in the lymph nodes where T cells bearing antigen-specific T cell receptors become activated². These tumor antigen-specific, activated T cells travel through the bloodstream to the tumor site, infiltrating the tumor and recognizing the cancer cells as foreign. Upon recognition, the T cells bind to the cancer cells and kill them, releasing more antigens and perpetuating the cycle. Nevertheless, the tumor microenvironment can create barriers that inhibit this process, such as immunosuppressive cells and molecules. Immunotherapies like checkpoint inhibitors and CAR-T cell therapy aim to overcome these barriers and enhance the effectiveness of the cancer immunity cycle, leading to better recognition and destruction of cancer cells by the immune system³.

Immune checkpoints are regulatory pathways in the immune system that maintain self-tolerance and modulate the duration and amplitude of physiological immune responses. Tumors can exploit these checkpoints to evade immune detection. The two primary immune checkpoints are CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4) and PD-1 (Programmed Death-1), and PD-L1/PD-L2 (Programmed Death-Ligand 1/2).CTLA-4 is expressed on T cells and competes with the co-stimulatory molecule CD28 for binding to CD80 and CD86 on APCs. By binding to these ligands, CTLA-4 inhibits T-cell activation and proliferation. On the other hand, PD-1 is expressed in T cells and binds to its ligands PD-L1 and PD-L2, which can be expressed by tumor cells and other cells in the tumor microenvironment. This interaction delivers an inhibitory signal to T cells, reducing their activity and promoting immune tolerance⁴. Immune checkpoint inhibitors are drugs designed to block these inhibitory pathways, thereby enhancing the immune response against cancer. The most well-known checkpoint inhibitors target CTLA-4 and PD-1/PD-L1 pathways⁵. These drugs can restore T cell activity and promote tumor destruction by inhibiting these checkpoints.

The effectiveness of cancer immunotherapy can vary based on several factors, including the type of cancer (indication), the genetic makeup of the tumor (genotype), and the immune environment of the cancer (immunotype)². Indication is defined by different types of cancers that respond differently to immunotherapy. For example, melanoma and non-small cell lung cancer (NSCLC) have shown significant responses to checkpoint inhibitors, while other cancers may be less responsive. Moreover, genotype refers to the genetic mutations present in a tumor that can influence its immunogenicity. Tumors with a high mutational burden tend to produce more neoantigens, which can be recognized by the immune system, making them more susceptible to immunotherapy. Finally, immunotype is the immune environment within the tumor, including various immune cells and cytokines, that can affect the response to immunotherapy. Tumors can be classified into different immunotypes based on their immune cell infiltration and cytokine profiles.

Despite the success of immune checkpoint inhibitors, several challenges persist. Not all patients respond to these therapies, and some may develop resistance over time. Understanding resistance mechanisms and identifying biomarkers to predict response are critical areas of ongoing research. In addition, combination therapies that target multiple steps of the cancer-immunity cycle or combine immunotherapy with other treatment modalities, such as chemotherapy or targeted therapy, are being explored to enhance efficacy and overcome resistance⁶.

The cancer-immunity cycle helps us understand the interactions between the immune system and cancer. Immune checkpoints are essential regulators of this cycle, and inhibiting them is an effective cancer treatment strategy. Ongoing research into factors like indications, genotype, and immunotype will continue improving cancer patients' immunotherapy outcomes.

References

1.    Raghani, N. R., Chorawala, M. R., Mahadik, M. et al. Revolutionizing cancer treatment: comprehensive insights into immunotherapeutic strategies.  Med. Oncol.   41, 51 (2024).

2.    Mellman, I., Chen, D. S., Powles, T., Turley, S. J. The cancer-immunity cycle: Indication, genotype, and immunotype.  Immunity   56, 2188-2205 (2023).

3.    Hoffmann, M. S., Hunter, B. D., Cobb, P. W., Varela, J. C., Munoz, J. Overcoming Barriers to Referral for Chimeric Antigen Receptor T Cell Therapy in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma.  Transplant Cell Ther.   29, 440-448 (2023).

4.    Zhang, H., Dai, Z., Wu, W. et al. Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer.  J. Exp. Clin. Cancer Res.   40, 184 (2021).

5.    de Miguel, M., Calvo, E. Clinical Challenges of Immune Checkpoint Inhibitors.  Cancer Cell   38, 326-333 (2020).

6.    Zhang, D., Zhao, J., Zhang, Y., Jiang, H., Liu, D. Revisiting immune checkpoint inhibitors: new strategies to enhance efficacy and reduce toxicity.  Front. Immunol.   15, 1490129 (2024).