Explain how PD-1/PD-L1 and CTLA-4 checkpoint inhibitors augment anti-tumor immunity, and name a potential toxicity.

• A. They block inhibitory signals on T cells, enhancing activation; toxicity: immune-mediated adverse events such as colitis or dermatitis.
• B. They directly kill tumor cells; toxicity: anemia.
• C. They suppress immune response; toxicity: infection risk.
• D. They inhibit T cells; toxicity: sedation.

Answer: (A)

Blocking inhibitory signals on T cells releases the brakes on anti-tumor immunity. PD-1 is an inhibitory receptor on T cells; when it engages PD-L1 or PD-L2, T cell activity is dampened and exhaustion can occur. Inhibitors of PD-1 or PD-L1 prevent this interaction, keeping T cells active, proliferating, and capable of attacking tumor cells. CTLA-4 acts earlier in T cell activation in lymph nodes by competing with CD28 for B7 ligands and delivering a negative signal; CTLA-4 inhibitors block this brake, allowing more robust initial activation of tumor-specific T cells. The combination of these effects amplifies the immune response against cancer.

A potential toxicity arises because unleashed T cells can attack normal tissues, leading immune-mediated adverse events such as colitis or dermatitis (more examples include pneumonitis, hepatitis, and endocrinopathies).