Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations

Abstract

Melanoma, a skin cancer associated with high mortality rates, is highly radio- and chemotherapy resistant but can also be very immunogenic. These circumstances have led to a recent surge in research into therapies aiming to boost anti-tumor immune responses in cancer patients. Among these immunotherapies, neutralizing antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are being hailed as particularly successful. These antibodies have resulted in dramatic improvements in disease outcome and are now clinically approved in many countries. However, the majority of advanced stage melanoma patients do not respond or will relapse, and the hunt for the "magic bullet" to treat the disease continues. This review examines the mechanisms of action and the limitations of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies which are the two types of checkpoint inhibitors currently available to patients and further explores the future avenues of their use in melanoma and other cancers.

Keywords: biomarkers; cancer; immune checkpoint inhibitors; immunotherapy; melanoma; mode of action; side effects.

Figures

Figure 1

Programmed cell death protein 1 (PD-1) mediated intracellular signaling events during T cell activation. (1) Upon T cell activation, the extracellular receptors PD-1, CD28, and the T cell receptor (TCR) complex (including CD4 or CD8) bind their ligands PD-L1 or PD-L2, CD80 or CD86, and major histocompatibility complex (MHC) class I or II, respectively. This brings all the receptors into close proximity with each other at the immunological synapse and allows them to interact with each other. (2) The Src kinase Lck (P56Lck), which is bound to the intracellular tail of CD4 and CD8, can now phosphorylate the tyrosine residues on the intracellular tails of PD-1 and CD28 as well as the CD3ζ chain of the TCR/CD3 complex. (3a) Phosphorylation of the immunoreceptor tyrosine-based switch motif (ITSM) motif on the intracellular tail of PD-1 allows recruitment of the Src homology region 2 domain-containing phosphatase 2 (SHP-2), resulting in the activation of SHP-2 phosphatase activity. SHP-1 may also bind PD-1 but to a lesser extent than SHP-2. (3b) Simultaneously, the phosphorylated tail of CD28 is now able to recruit PI-3K and Grb2 among other signaling molecules. (4) Through close proximity at the immunological synapse, PD-1-associated SHP-2 can dephosphorylate the cytoplasmic tail of CD28, and to a lesser extent that of the CD3ζ chain, therefore preventing the recruitment of further downstream signaling molecules associated with these molecules. SHP-2 may also dephosphorylate PD-1, causing auto-regulation of this inhibitory pathway. (5) CD28 provides critical signals alongside TCR stimulation, and the abrogated binding of PI3K and Grb2 to this receptor therefore leads to decreased signaling in pathways important for IL-2 production, survival, proliferation, and certain effector functions. In the absence of its ligands, PD-1 is not recruited to the immune synapse and can therefore not interfere with activation signaling. (6) The inhibitory receptor CTLA-4 primarily restricts CD28 signaling indirectly by reducing the availability of CD80 and CD86, to which it binds with a much higher affinity than the co-stimulatory receptor CD28. Sources (–45).

Figure 2

The role of programmed cell death protein 1 (PD-1) and T-lymphocyte-associated protein 4 (CTLA-4) in the priming and effector phases of anti-tumor immune responses. For T cell priming, dendritic cells (DCs) sample antigen at the tumor site and transport it to the draining lymph nodes, where they present the antigens on their major histocompatibility complex (MHC) molecules to T cells. T cells become activated if their T cell receptors recognize and bind the antigen on MHC complexes and their CD28 costimulatory receptors bind CD80 and CD86 on DCs. CTLA-4 upregulation on T cells or bystander Tregs can interfere with the CD28 signal, as the former receptor binds CD80 and CD86 with higher affinity. Once activated, T cells migrate to the tumor site in order to kill malignant cells. Tumors or bystander cells such as macrophages may, however, upregulate PD-L1 and therefore obstruct T cell function by inducing inhibitory intracellular signaling. Anti-CTLA-4 blocking antibody may therefore restore T cell priming in the lymph nodes, and the PD-1 signaling blockade may enable T cell effector function at the tumor site. Additionally, other cell types such as Breg cells and DCs in the tumor microenvironment may express PD-1 and therefore be affected by PD-1 blockade. PD-1 and CTLA-4 blockade may also affect T helper cell profiles directly or by influencing the microbiota.