Learning Objective

By the end of this section, learners should be able to explain how immune checkpoint pathways regulate T-cell activation and how checkpoint inhibitors enhance antitumor immune responses.

Immune checkpoints are regulatory pathways that modulate T-cell activation and function, thereby downregulating immune responses to maintain self-tolerance and prevent excessive inflammation. Tumor cells exploit these pathways to evade immune destruction. Several modern cancer immunotherapies target these checkpoint interactions to restore effective antitumor immunity.

Key Immune Checkpoint Pathways

PD-1 / PD-L1 Pathway

• PD-1 is an inhibitory receptor expressed on activated T cells.
• PD-L1 and PD-L2 are expressed on tumor cells and immune cells within the tumor microenvironment.
• Interaction of PD-1 with PD-L1/2 leads to T-cell dysfunction (T-cell exhaustion), reducing cytotoxic activity against tumor cells.

Therapeutic inhibition:

• Anti-PD-1 antibodies: cemiplimab, nivolumab, pembrolizumab
• Anti-PD-L1 antibodies: atezolizumab, durvalumab, avelumab

Blocking this interaction restores T-cell effector function and enhances tumor cell killing.

CTLA-4 Pathway

• CTLA-4 is an inhibitory receptor on T cells that competes with CD28 for binding to B7 (CD80/CD86) on antigen-presenting cells (APCs).
• CTLA-4 has a higher affinity for B7 than CD28, resulting in loss of T-cell costimulatory signaling and decreased T-cell activation.

Therapeutic inhibition:

• Anti-CTLA-4 antibody: ipilimumab

Blocking CTLA-4 enhances early T-cell activation and proliferation.

Activity

High-Yield Exam Pearl

• PD-1 inhibitors reverse T-cell exhaustion in peripheral tissues
• CTLA-4 inhibitors enhance T-cell activation at the priming phase in lymph nodes

Activity

Activity