Which feature characterizes tumors that respond well to immune checkpoint inhibitors, particularly in MSI-H settings?

• A. High mutational burden and neoantigen load.
• B. Low mutation burden.
• C. Absence of T cell infiltration.
• D. Lack of PD-1 expression.

Answer: (A)

The main concept here is how the immune system recognizes cancer and how that recognition is boosted by high mutation-derived signals. When tumors accumulate many mutations, they generate neoantigens that look foreign to T cells. This makes the cancer more visible to the immune system. Microsatellite instability–high (MSI-H) tumors have defects in mismatch repair, leading to a particularly high number and variety of mutations, so they present many neoantigens. Immune checkpoint inhibitors work by releasing the brakes on T cells, allowing them to attack these neoantigen-rich tumors more effectively. So the feature that characterizes tumors that respond well, especially in MSI-H settings, is a high mutational burden and neoantigen load.

Low mutation burden means fewer neoantigens and less T cell targeting, so responses are less likely. Absence of T cell infiltration suggests the immune system isn’t present to be reinvigorated. Lack of PD-1 expression would reduce the direct target for PD-1 inhibitors, limiting their effectiveness in that axis.