Immune Checkpoint Molecules: A Review on Pathways and Immunotherapy Implications

Abstract

Background: Today, treating cancer patients with monoclonal antibodies (mAbs), by targeting immune checkpoints, is one of the most outstanding immunotherapeutic methods. Immune checkpoints are special molecules having regulatory role in immune system responses. Once these molecules are presented on cancer cells, these cells will be capable of evading the immune system through their own specific pathways. This Evasion can be prevented by counterbalancing immune system responses with immune checkpoints related antibodies.

Aims: The current study aimed to highlight immunotherapy and its methods, describe the immune checkpoints pathways, outline the immune checkpoint inhibitors (ICIs), and recent advances in this field, and sketch an outlook on the best treatment options for the most prevalent cancers.

Materials & methods: This research implemented a narrative review method. A comprehensive literature review on the history, molecular and cellular biology, and the clinical aspects of immune checkpoint molecules was performed to illustrate the pathways involved in various cancers. Also, currently-available and future potential immunotherapies targeting these pathways were extracted from the searched studies.

Results: The immune checkpoint family consists of many molecules, including CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, and TIGIT. Attempts to modify these molecules in cancer treatment led to the development of therapeutic monoclonal antibodies. Most of these antibodies have entered clinical studies and some of them have been approved by the Food and Drug Administration (FDA) to be used in cancer patients' treatment plans.

Discussion: With these novel treatments and the combination therapies they offer, there is also hope for better treatment outcomes for the previously untreatable metastatic cancers. In spite of the beneficial aspects of immune checkpoint therapy, similar to other treatments, they may cause side effects in some patients. Therefore, more studies are needed to reduce the probable side effects and uncover their underlying mechanism.

Conclusion: Based on the data shown in this review, there is still a lack of knowledge about the complete properties of ICIs and the possible combination therapies that we may be able to implement to achieve a better treatment response in cancer patients.

Keywords: CTLA‐4; PD‐1; PD‐L1; immune checkpoint inhibitor (ICI); immune modulators; immunotherapy.

Figure 1

Inhibition of T‐cell activation. In T cell activation, CK2 phosphorylates PTEN. PTEN inhibits PI3K, which leads to the dephosphorylation of PIP3 to generate PIP2, making PIP3 less available in the cell. Therefore, T cell activation results in a reduction of PI3K inhibition. PD‐1 inhibits the phosphorylation of PTEN and stimulates PTEN phosphatase activity by inhibiting CK2, thus terminates PI3K/Akt pathway initiation. Therefore, T cell proliferation will decrease. SHP‐2 binds to the cytoplasmic tail of PD‐1 from the site of ITSM. Another signaling pathway that PD‐1 affects is the Ras/MEK/ERK pathway. MEK‐ERK pathway is downstream to Ras, and Ras signaling pathway is important for T cell development, proliferation, and differentiation. Ras includes diacylglycerol (DAG)‐binding domain and a couple of calcium‐binding EF‐hands. PLCγ1 hydrolyzes PIP2, resulting in DAG and IP3 generation. IP3 stimulates release of calcium from intracellular stores. DAG and Ca²⁺ are necessary for the activation of RasGRP1. Hence, PLCγ1 activation brings about RasGRP1 activation. PD‐1 has the ability of PLCγ1 inhibition, and actually, PD‐1 inhibits TCR linkage to Ras and restricts T cell development, proliferation, and differentiation. Parts of this figure were created using the freely available samples on https://smart.servier.com/; the full figure is an original take from the authors.