Immune checkpoint blockade opens an avenue of cancer immunotherapy with a potent clinical efficacy

Abstract

Recent progress in tumor immunology has revealed that tumors generate immunologically restrained milieu during the process of their growth, which facilitates the escape of tumors from host immune systems. Immune checkpoint molecules, which transduce co-inhibitory signals to immuno-competent cells, are one of the most important components conferring the immunosuppressive capacity in the tumor microenvironment. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) are typical immune checkpoint molecules intimately involved in the suppression of anti-tumor immunity. Antibodies against those molecules have been developed, such as ipilimumab (anti-CTLA-4 antibody), nivolumab and pembrolizumab (anti-PD-1 antibody), and have been approved by regulatory agencies and used in some countries. Treatment with these antibodies demonstrates previously unobserved clinical efficacies superior to the conventional therapies. In this review, we first discuss the escape mechanisms of cancer from host immune systems, and then focus on the recent advances in immune checkpoint blockade therapy and on the new findings of related immune reactions, aiming to provide a better understanding of the novel cancer immunotherapies.

Keywords: Anti-PD-L1 Ab; PD-1/PDL-1 pathway; cancer immunoediting; cancer immunosurveillance; immune checkpoint molecules.

Figure 1

Immunosurveillance and cancer immunoediting. Although gene mutations and resultant generations of cancerous mutant cells routinely occur in a body, the immunosurveillance system detects and eliminates these mutant cells in most cases by trapping them into immunological filters. However, the strong selective pressure by the immune system itself engenders further oncogenic cells, which are inherently immune-resistant and, thus, slip through the immunological filters. Such changes in the immunogenicity of tumors are referred to as cancer immunoediting. Once the mutant cells procure the features with which they prevail over the tumoricidal effects of host immunity, those cells can expand and generate tumors.

Figure 2

Regulation of T cell responses by stimulatory and inhibitory co-signals. While T cell receptor (TCR) transduces “the first signal” into T cells, co-signaling receptors deliver “the second signal.” When stimulatory co-signals are predominant over inhibitory co-signals, the T cells activate to proliferate, produce cytokines and/or exert cytotoxic activities. In contrast, when inhibitory co-signals are predominant, T cells are rendered inactivated and become unresponsive to Ags, a status referred to as immune tolerance or exhaustion. A fine regulation of T cell functions by balancing stimulatory and inhibitory co-receptors routinely takes place in hosts to maintain immunological homeostasis.

Figure 3

Conceptual diagram of cancer immunotherapy with immune checkpoint blockade. (a) The aim of cancer immunotherapies is to make the balance of the host immunity biased toward the stimulation-dominant side while the balance is strikingly biased toward the inhibition-dominant side in the tumor microenvironment. (b) In conventional immunotherapy, the immunological balance is readjusted by “putting the weight on the stimulatory side.” Yet, in many cases, such approaches cannot overcome the potent immunosuppressive mechanisms in the tumor microenvironment. (c) In immune checkpoint blockade therapy, the balance is readjusted by “decreasing or removing the weight from the inhibitory side.”

Figure 4

Distinct phases in which CTLA-4 and PD-1 express immune checkpoint functions. When T cells are primed by interactions with antigen-presenting cells in the lymph node, expression of CTLA-4 is upregulated to prevent or shut down excessive T cell responses. Meanwhile, the activated T cells differentiate into effector cells, migrate to tumor tissue, and attack the target cells. During this process, T cells upregulate PD-1 expression, which renders them susceptible to the immune inhibition by PD-L1, which is highly expressed in the tumor microenvironment. Collectively, CTLA-4 is the immune checkpoint molecule working at the early phase of T cell activation, while PD-1 is the one at the later phase when the effector functions are exerted.