Immune Checkpoint Blockade: Immunotherapies in Cancer Treatment

Checkpoint inhibitors are a type of cancer immunotherapy that work by blocking inhibitory pathways in the immune system, thereby enhancing the ability of the immune system to recognize and attack cancer cells. These therapies target specific interactions between inhibitory costimulatory molecules on T cells and their ligands on tumor cells or other immune cells. The most widely studied checkpoint inhibitors target two main pathways: the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway and the programmed cell death protein 1 (PD-1) pathway.

1. CTLA-4 Inhibitors: CTLA-4 is a coinhibitory receptor expressed on activated T cells that competes with CD28 for binding to B7 molecules (CD80/CD86) on antigen-presenting cells (APCs). When CTLA-4 engages with B7 molecules, it delivers inhibitory signals to T cells, dampening immune responses. CTLA-4 inhibitors, such as ipilimumab, block the interaction between CTLA-4 and B7 molecules, thereby enhancing T cell activation and proliferation. By releasing the brake on T cell activation, CTLA-4 inhibitors can unleash the immune system’s ability to recognize and attack cancer cells.
2. PD-1/PD-L1 Inhibitors: Programmed cell death protein 1 (PD-1) is another coinhibitory receptor expressed on T cells that interacts with its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), expressed on tumor cells or other immune cells. PD-1 engagement with PD-L1 or PD-L2 delivers inhibitory signals to T cells, leading to T cell exhaustion, anergy, or apoptosis, thereby allowing cancer cells to evade immune surveillance. PD-1/PD-L1 inhibitors, such as pembrolizumab, nivolumab, and atezolizumab, block the interaction between PD-1 and PD-L1/PD-L2, thereby restoring T cell function and enabling immune-mediated tumor clearance.

These checkpoint inhibitors aim to overcome immune evasion mechanisms employed by cancer cells and reinvigorate antitumor immune responses. By targeting specific interactions between inhibitory costimulatory molecules and their ligands, checkpoint inhibitors unleash the immune system’s ability to recognize and eradicate cancer cells, leading to durable and often long-lasting responses in some cancer patients. However, it’s important to note that not all patients respond to checkpoint inhibitors, and further research is ongoing to identify biomarkers predictive of response and to develop combination therapies to improve outcomes for cancer patients.

End of Unit 3

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Source: ChatGPT response prompted and edited by Joel Graff.

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