Researchers are conducting a study to determine the effectiveness of a novel humanized monoclonal antibody in patients with metastatic colorectal cancer. This medication works by binding to the programmed cell death-1 receptor on T cells to block its ligands from binding. They find this therapy is most effective in patients with a high degree of microsatellite instability or defects in DNA mismatch repairs. Which of the following best explains the favorable drug effect in this subset of patients?

Question

Researchers are conducting a study to determine the effectiveness of a novel humanized monoclonal antibody in patients with metastatic colorectal cancer.  This medication works by binding to the programmed cell death-1 receptor on T cells to block its ligands from binding.  They find this therapy is most effective in patients with a high degree of microsatellite instability or defects in DNA mismatch repairs.  Which of the following best explains the favorable drug effect in this subset of patients?

Quizplus · Accepted Answer

The genetic mutations that drive oncogenesis also create unique proteins not found in healthy cells. Antigens from these proteins (neoantigens) are displayed on the surface of tumor cells and may be subsequently recognized by patrolling cytotoxic T cells as "not-self" and destroyed. Cancers with defects in mismatch repair proteins and high microsatellite instability (reflecting DNA polymerase errors during cellular replication) are particularly susceptible to immune recognition because they rapidly accumulate mutations and generate approximately 20-fold more neoantigens than tumor cells that have normal mismatch repair. Cancer cells use a wide range of mechanisms to thwart cytotoxic T-cell detection, including: Downregulating cell surface receptors involved in immune recognition. For instance, decreased expression of the major histocompatibility complex leads to decreased neoantigen presentation on the surface of the cell. Overexpressing cell surface proteins that inhibit the immune response. For instance, cancer cells can overexpress programmed death-ligand 1 (PD-L1), which binds to the programmed cell death-1 (PD-1) receptor on the T-cell surface and inhibits the cytotoxic T-cell response (T-cell exhaustion). Cancer cells that overexpress PD-L1 are less susceptible to cytotoxic T-cell-mediated destruction (enhanced T-cell exhaustion). These tumors can be treated with monoclonal antibodies that block the PD-1 receptor on T cells (eg, pembrolizumab, nivolumab) or the PD-1 ligand on cancer cells (eg, atezolizumab). Treatment stimulates the cytotoxic T-cell response; it is particularly effective against tumors with large quantities of neoantigens (eg, those with deficits in mismatch repair) because these tumors are particularly susceptible to recognition as "not-self." (Choice A) P-glycoprotein is a multidrug transporter that can be used by cancer cells to pump cytotoxic chemotherapy out of the cell. (Choice C) KRAS is a proto-oncogene that is part of the signaling pathway for the epidermal growth factor receptor. Activating mutations in KRAS lead to unregulated cellular growth. Tumors with activating mutations to KRAS are resistant to monoclonal antibodies against epidermal growth factor receptor because they have an activating mutation in a downstream signal. (Choice D) p53 is a tumor-suppressor protein that inhibits cellular replication when DNA is damaged and induces apoptosis. Mutations to p53 can lead to unregulated cellular growth and may inhibit cytotoxic chemotherapy-mediated cancer cell apoptosis. (Choice E) Desmoplasia (dense fibrosis) around a tumor can reduce the ability of cytotoxic chemotherapy to enter cancer cells. Educational objective: Cancer cells avoid immune recognition by overexpressing programmed death-ligand 1 (PD-L1), which binds to the programmed cell death-1 (PD-1) receptor on cytotoxic T cells and inhibits their response (T-cell exhaustion). Monoclonal antibodies that block PD-L1 and PD-1 are effective against cancers that express high levels of neoantigens on their surface because these tumors are particularly susceptible to immune recognition by cytotoxic T cells. __________ References: PD-1 blockade in tumors with mismatch-repair deficiency. (http://www.ncbi.nlm.nih.gov/pubmed/26028255)

Researchers Are Conducting a Study to Determine the Effectiveness of a Novel