CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients (1)
A number of inhibitory receptors and ligands expressed on T cells, antigen presenting cells (APC), and tumor cells have recently been identified as targets for cancer immunotherapy as they are critical mediators of immune suppression in the tumor microenvironment.
CTLA-4 outcompetes the stimulatory receptor CD28 for binding to its ligands (CD80/CD86) due to its higher binding affinity and delivers a negative signal into the T cell, leading to inhibition of T-cell activation and expansion. CTLA-4 regulates T cells predominantly during initial activation by dendritic cells and other APCs (priming phase). Furthermore, CTLA-4 is expressed by regulatory T cells (Treg) and memory CD4 cells and these cells may also be targeted by CTLA-4 blockade.
Whereas CTLA-4 is operational during early activation of T cells in lymphatic tissues, another regulatory molecule expressed on T cells, programmed death-1 (PD-1), functions during the effector phase of T-cell activation. The interaction of PD-1 with its two ligands, B7-H1 and B7-DC (PD-L1 and PD-L2), occurs predominantly in peripheral tissues including the tumor microenvironment and leads to apoptosis and downregulation of T-cell effector function. The engagement of PD-1/PD-L1 interaction decreases the risk of collateral tissue damage by T cells. An antibody directed against PD-1, which only blocks interactions between PD-1 and its two ligands PD-L1 and PD-L2 (B7-DC), does not block the inhibitory signal through B7.1. Similarly, an antibody directed against PD-L1 blocks the inhibitory signals through PD-1 and B7.1, but does not affect the PD-L2-PD-1 pathway. The different biology that is likely associated with inhibition of these distinct sets of receptor–ligand interactions should be taken into consideration when designing and evaluating clinical trials with PD-1- and PD-L1–directed antibodies.
PD1 interaction with its ligands mostly occurs in peripheral tissues and organs, upon re-presentation of antigens to memory T cells. Naïve T cells are endowed with a set of adhesion molecules that allow them to extravasate through high endothelial venules (HEV) and to reach T-cell–dependent areas of the lymph nodes where antigens are brought via afferent lymphatics, processed, and carried by APCs. If the antigen is presented to the T cell harboring the corresponding receptor, T-cell activation will occur, implicating the costimulation molecules.
in the context of immunoediting: (i) PD-1 blockade, similar to CTLA-4 inhibition, has the potential to establish a favorable equilibrium between adequate T-cell response against the tumor and immune evasion by the tumor; (ii) tumor recurrence after successful treatment with PD-1 blockade indicates disruption of this equilibrium; and (iii) retreatment with PD-1 inhibition after recurrence can reset this balance.
PD-L1 expression by the tumor is actively being pursued as a predictive marker for tumor activity of PD-1– and PD-L1–directed antibodies. In BRAFV600 mutant tumors, BRAF/MEK inhibition has also revealed promising antitumor activity. Additional potential complementary immune therapies include adoptive T-cell transfer, vaccines, suppression of Tregs or the blockade of other inhibitory checkpoints such as Tim-3, LAG-3, and B7-H3, among others.
In a B16 melanoma model, inhibition of CTLA-4 leads to a higher proportion of tumor-infiltrating cells (TIL) expressing PD-1, whereas PD-1 blockade leads to upregulation of CTLA-4 on TIL. Antitumor activity of CTLA-4 blockade may be dampened by suppression of tumor-specific T effector cells through the PD-L1/PD-1 pathway in the tumor and that this immune suppression is partially mediated by the CTLA-4 blockade itself. Conversely, the efficacy of PD-1 blockade may be compromised by the lack of full activation of tumor-specific effector T cells mediated by CTLA-4, which also may be aggravated by upregulation of CTLA-4 induced by the PD-1 inhibition itself. Therefore, monotherapy with either CTLA-4 or PD-1 blockade leaves the other critical immune checkpoint unopposed and may induce further upregulation of a compensatory regulatory pathway. Substantial synergy may therefore arise by blockade of both checkpoints.