Why do PD-1 inhibitors tend to have higher response rates in tumors with mismatch repair deficiency (dMMR) or MSI-H?

• A. Increased mutational burden yields more neoantigens.
• B. They inherently express higher PD-L1 on tumor cells, making them more susceptible to PD-1 blockade.
• C. They have a lower mutation burden which paradoxically increases response.
• D. They respond better because they are more vascularized.

Answer: (A)

High mutational burden from mismatch repair deficiency or MSI-H increases the number of neoantigens presented by tumor cells. These new, abnormal peptides stand out to the immune system, making the cancer more recognizable to T cells. PD-1 inhibitors lift the brakes on those T cells, allowing a stronger attack specifically against cells presenting those neoantigens. That combination—more foreign-looking targets plus relief of inhibitory signals—explains why PD-1 blockade tends to work better in dMMR/MSI-H tumors. The other ideas don’t fit as well: simply having higher PD-L1 expression isn’t the consistent predictor, a lower mutation burden would reduce neoantigen targets, and vascularization isn’t the primary driver of this response.