Researchers are investigating the use of immune checkpoint inhibitors for the treatment of advanced colorectal cancer. They find that this therapy is more effective in patients with DNA mismatch-repair deficiency compared to patients with an intact mismatch-repair mechanism. Which of the following most likely explains the improved efficacy of the drug in the first group of patients?

Question

Researchers are investigating the use of immune checkpoint inhibitors for the treatment of advanced colorectal cancer.  They find that this therapy is more effective in patients with DNA mismatch-repair deficiency compared to patients with an intact mismatch-repair mechanism.  Which of the following most likely explains the improved efficacy of the drug in the first group of patients?

Quizplus · Accepted Answer

DNA mismatch repair (MMR) is a highly conserved pathway that maintains genomic integrity by correcting base-base mismatches and insertions/deletions during DNA replication, recombination, or repair. Loss of MMR in germline cells is a common driver of malignancy (eg, colorectal cancer) because it leads to the development of unrepaired oncogenic mutations during cellular division, which accumulate through generations of cellular progeny. Mutations in genes that control apoptosis, cellular growth, and epigenetics eventually lead to malignant transformation. Cancer cells with damaged MMR typically contain >1,000 somatic coding mutations, whereas cancer cells with intact MMR usually have only 40-50 (Choice E). MMR impairment greatly increases the rate of frameshift mutation, resulting in the formation of large quantities of neoantigens not seen in healthy cells. These neoantigens are displayed on class I major histocompatibility complexes (MHCs) on the cancer cell surface, leading to the activation of a diverse, polyclonal pool of antitumor cytotoxic T cells. Therefore, in order to survive and proliferate, malignant cells with impaired MMR are particularly dependent on adaptations to avoid cytotoxic T-cell-mediated destruction; these adaptations typically include downregulating expression of class I MHCs (Choice B), which impairs identification of the cancer cell by cytotoxic T cells, and overexpressing immune checkpoint molecules (eg, CTLA4, PD-L1), which impairs T-cell activation and effector function. Although no approved therapy targets diminished class I MHC expression, treatment with immune checkpoint inhibitors (eg, ipilimumab, pembrolizumab) can restore cytotoxic T-cell function in the tumor microenvironment, leading to aggressive antitumor activity. (Choice C) Regulatory T cells suppress immune activity with surface receptors (eg, CTLA4) and cytokines (eg, IL-10, TGF-beta). Increased regulatory T cells in the tumor microenvironment is associated with poor prognosis, but MMR mutations are not associated with regulatory T-cell recruitment. (Choice D) Metalloproteinases allow tumor cells to open a channel through the basement membrane and dislodge from their site of origin. This is an important component of metastasis but is not strongly associated with MMR deficiency. Educational objective: Because tumors with defective DNA mismatch repair generate high levels of neoantigens, they are particularly dependent on adaptations (eg, overexpression of immune checkpoints) to avoid cytotoxic T-cell destruction. Treatment with immune checkpoint inhibitors restore antitumor cytotoxic T-cell activity and often dramatically reduce tumor burden.

Researchers Are Investigating the Use of Immune Checkpoint Inhibitors for the Treatment