How do CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), PD-1 (Programmed Death-1), and PD-L1 (Programmed Death-Ligand 1) regulate the immune response?

Mechanisms of CTLA-4, PD-1, and PD-L1 in Immune Regulation

CTLA-4 and PD-1 are inhibitory checkpoint molecules expressed on T cells that suppress immune responses at different stages and locations, while PD-L1 is a ligand expressed on tumor cells and antigen-presenting cells that binds to PD-1 to inhibit T-cell activity. 1

CTLA-4 Mechanism

CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) functions early in the immune response, primarily in lymph nodes, to regulate T-cell activation and proliferation. 2

• CTLA-4 is expressed on activated T cells and enforces an activation threshold that attenuates proliferation of tumor-specific T lymphocytes 3
• The molecule competes with the co-stimulatory receptor CD28 for binding to shared ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells 4
• CTLA-4 actively removes CD80 from the surface of antigen-presenting cells through a process called transendocytosis, where CTLA-4 captures and degrades its ligands 5
• This transendocytosis is highly specific—only CD80 is internalized while other molecules like PD-L1 remain on the cell surface 5
• By removing co-stimulatory signals, CTLA-4 prevents T-cell proliferation and limits the initial expansion of immune responses 2

PD-1 Mechanism

PD-1 (Programmed Death-1) is a checkpoint receptor that suppresses T cells later in the immune response, primarily in peripheral tissues and the tumor microenvironment. 2

• PD-1 is expressed on activated T cells and functions as a "stop signal" that limits T-cell effector function within tumors 3
• PD-1 binds to two ligands: PD-L1 (programmed death ligand 1) and PD-L2 1
• When PD-1 is engaged by its ligands, T-cell activity is suppressed, including cytotoxic T-cell activity, T-cell proliferation, and cytokine production 6
• PD-1 acts at a different phase than CTLA-4—it inhibits already-activated T cells in tissues rather than preventing initial activation in lymph nodes 2

PD-L1 Mechanism

PD-L1 is a co-regulatory molecule expressed on tumor cells and tumor-infiltrating immune cells that inhibits T-cell-mediated cell death by binding to PD-1. 7

• PD-L1 binds to both PD-1 and B7.1 receptors found on T cells and antigen-presenting cells, suppressing cytotoxic T-cell activity 6
• In various tumors including lung cancer, PD-L1 is often overexpressed on tumor cells and plays an important role in modulating the immune response 7
• PD-L1 expression on tumor cells and cells within the tumor microenvironment represents a mechanism through which tumors eliminate PD-1-positive T cells 1
• The PD-L1/PD-1 interaction contributes to inhibition of the anti-tumor immune response in the tumor microenvironment 6

Interplay Between Pathways

CTLA-4 can indirectly regulate PD-L1:PD-1 interactions through its control of CD80. 5

• CD80 and PD-L1 form a physical heterodimeric interaction that blocks PD-L1 from binding to PD-1 5
• When CTLA-4 removes CD80 via transendocytosis, PD-L1 availability recovers in a time-dependent manner, allowing PD-L1 to bind PD-1 and suppress T-cell function 5
• This mechanism demonstrates that CTLA-4 acts as a modulator of PD-L1:PD-1 interactions via control of CD80 5

Clinical Implications

The distinct mechanisms and sites of action suggest that blocking CTLA-4 and PD-1/PD-L1 pathways produces different but complementary therapeutic effects. 2

• Combination blockade of both CTLA-4 and PD-1 resulted in a 53% objective response rate in melanoma patients, compared to monotherapy 1
• CTLA-4 blockade (ipilimumab) primarily enhances T-cell priming and proliferation in lymphoid organs 3
• PD-1/PD-L1 blockade primarily restores T-cell effector function within the tumor microenvironment 8
• The independent mechanisms of action explain why combined anti-CTLA-4 and anti-PD-1 therapy offers more potent anti-tumor activity than either agent alone 3

Important Caveats

• PD-1 inhibitors cause more immune-related adverse events than PD-L1 inhibitors, particularly pneumonitis (4% vs 2%) and hypothyroidism (6.7% vs 4.2%) 8
• Combined CTLA-4 plus PD-1 blockade causes substantially more high-grade immune-related adverse events (55-60%) compared to PD-1 monotherapy (10-20%) 8
• Treatment discontinuation due to adverse events occurs in 39% with combination therapy versus 12% with PD-1 monotherapy 8