BLOCKADE Classic [hack]l
Francoise Witsell
Immune checkpoint molecules are promising anticancer targets, among which therapeutic antibodies targeting the PD-1/PD-L1 pathway have been widely applied to cancer treatment in clinical practice and have great potential. However, this treatment is greatly limited by its low response rates in certain cancers, lack of known biomarkers, immune-related toxicity, innate and acquired drug resistance, etc. Overcoming these limitations would significantly expand the anticancer applications of PD-1/PD-L1 blockade and improve the response rate and survival time of cancer patients. In the present review, we first illustrate the biological mechanisms of the PD-1/PD-L1 immune checkpoints and their role in the healthy immune system as well as in the tumor microenvironment (TME). The PD-1/PD-L1 pathway inhibits the anticancer effect of T cells in the TME, which in turn regulates the expression levels of PD-1 and PD-L1 through multiple mechanisms. Several strategies have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including combination therapy with other standard treatments, such as chemotherapy, radiotherapy, targeted therapy, anti-angiogenic therapy, other immunotherapies and even diet control. Downregulation of PD-L1 expression in the TME via pharmacological or gene regulation methods improves the efficacy of anti-PD-1/PD-L1 treatment. Surprisingly, recent preclinical studies have shown that upregulation of PD-L1 in the TME also improves the response and efficacy of immune checkpoint blockade. Immunotherapy is a promising anticancer strategy that provides novel insight into clinical applications. This review aims to guide the development of more effective and less toxic anti-PD-1/PD-L1 immunotherapies.
Immunotherapy, a promising anticancer strategy that improves the specificity and strength of the immune response to cancer, has been widely studied in recent years. Brakes on the immune system protect healthy tissues and organs from attack by the immune system; this brake system is hijacked by cancer cells to escape from the immune system or even turn against it [1]. The programmed cell death 1 receptor (PD-1)/programmed cell death ligand 1 (PD-L1) pathway and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway constitute the well-known brake system of the immune system. Targeting these two pathways has been shown to be a successful anticancer strategy [2]. Antibodies against the PD-1/PD-L1 pathway have been extensively applied to cases of melanoma, lung cancer, lymphoma, liver cancer, colorectal cancer, urothelial cancer, squamous cell carcinoma of the head and neck, cervical cancer, kidney cancer, stomach cancer and breast cancer [3]. This monotherapy or combination therapy (as adjuvants or neo-adjuvants) produces a remarkable clinical response. A small number of cancer patients subsequently experience long-term remission. Nevertheless, the PD-1/PD-L1 blockade, similar to other anticancer treatments, is also limited by a low response rate in certain cancers, lack of known biomarkers, immune-related toxicity and innate and acquired drug resistance. To date, the clinical response to PD-1/PD-L1 blockade is barely 40% [4]. Thus, identifying optimal biomarkers for screening cancer patients who are responsive to immune checkpoint blockades (ICBs) and accurately monitoring its therapeutic efficacy is of great clinical importance [5]. In addition, it is important to precisely distinguish cancer cells from normal cells in ICBs, thus preventing severe adverse events such as discontinued treatment, dose reduction or even death due to immune-related toxicity [6]. Similar to other anticancer treatments, some patients may not be sensitive to ICB or develop drug resistance after a period of medication. Elucidating the potential mechanisms of low responses and drug resistance to ICB will enhance their clinical benefits [7] and is key to improving the efficacy of immunotherapy [8].
In the present review, we first illustrate the biological mechanisms of PD-1/PD-L1 immune checkpoints and their role in both the normal immune system and TME, aiming to enhance current understanding of the immune checkpoint molecules PD-1/PD-L1. Combination therapy with other standard treatments, such as chemotherapy, radiotherapy, targeted therapy, anti-angiogenic therapy, other immunotherapies and even diet control, is expected to address the limitations of PD-1/PD-L1 blockade. Either upregulation or downregulation of PD-L1 expression in the TME improves the therapeutic efficacy of ICBs; a combination therapy of either with immunotherapy may represent a novel anticancer treatment and combinatorial drug design. This review summarizes the latest developments, prospects and challenges of the combination therapy of PD-1/PD-L1 blockade and PD-L1 regulation, aiming to provide novel ideas for developing more effective and less toxic anti-PD-1/PD-L1 immunotherapy.
Advanced cancer has mainly been treated with radiotherapy and chemotherapy in recent decades. However, these treatments are unable to distinguish normal cells from cancer cells, leading to damage of normal cells, severe adverse events and even discontinuation of treatment. The normally functioning immune system is capable of accurately recognizing and eliminating cancer cells due to significant differences between normal cells and cancer cells, thus achieving precision killing. The interaction between cancer cells and the immune system used to be considered the main determinant factor for carcinogenesis [9].
However, recent evidence has shown that most new tumors formed in the esophagus would naturally be eliminated due to the weaker viabilities of these newly formed tumors that of adjacent mutant epithelial cells, rather than differences in survival due to the involvement of the immune system [10]. Mutations are the potential origin of cancers. It was recently found that carcinogenicity is mediated by oncogenes (e.g., BRAFV600E), lineage-specific transcription factors (e.g., SOX10) and chromatin factors for regulating development (e.g., ATAD2) [11].
A recent study analyzed the relationship between immune response and tumor development [12], finding that chronic inflammatory cells secrete IL-6 and that transient inflammation leads to persistent reprogramming of epithelial cells leading to subsequent tumorigenesis, thus underscoring the role of the immune system in promoting tumorigenesis. Established anti-tumor immune responses suppress tumor development, but tumor cell clones that escape immune surveillance eventually develop into clinically visible tumors.
Cancer immunotherapy eliminates cancer cells by stimulating and enhancing immune function or regulating the immune state based on immune surveillance and immune editing. Of all immune cells, T cells are the most powerful tool for directly killing cancer cells and are characterized by high specificity, strong memory and high adaptability [13]. The cancer-immunity cycle, in which cancer cells release specific antigens and the immune system is activated to kill them, is a cyclical process involving 7 steps: (1) Antigens are expressed and released by cancer cells; (2) cancer antigen processing and presentation; (3) T cell initiation and activation; (4) T cell migration to cancer lesions; (5) T cell penetration to cancer lesions; (6) recognition of cancer cells by T cells; and (7) elimination of cancer cells by T cells [14]. Multiple factors in this cancer-immunity cycle are potential therapeutic targets for immunotherapies. Cancer cells have been reported to express high levels of immunosuppressive signal proteins, which contribute to avoid the attack of immune cells in the TME.
T cells are the most important part of the immune system, and their function is strictly and precisely regulated by the immune system, as multiple receptor molecules on the cell membrane transduce activating or inhibitory signals. Once T cells are activated by antigen stimulation, the immune system also initiates negative feedback to avoid continuous overactivation of T cells that causes excessive damage to the body. Inhibitory receptor molecules, known as checkpoint molecules, expressed on the surface of T cells are responsible for the negative feedback of the immune system, inhibiting the elimination of target cells by T cells by binding corresponding ligand molecules on the target cell surface. Checkpoint molecules are well studied in translational research in immunotherapies [15].
Immune checkpoint inhibitors (ICIs) have recently been highlighted for their functions in blocking the effect of inhibitory immune molecules on T cells and thus reducing immune tolerance to cancers; these ICIs have been widely analyzed by biopharmaceutical companies. Many immune checkpoints have been identified, including CTLA-4 and PD-1; while both have been thoroughly investigated, PD-1 has been of particular interest and has been widely applied in clinical practice.
PD-1 is a cell surface receptor that was initially found to be preferentially expressed in apoptotic cells [16]. Later, PD-1 was identified as the key immune checkpoint for regulating T and B cell response thresholds to antigens. As a key checkpoint for T cells, PD-1 exerts a central role in regulating their cellular functions. The interaction between PD-L1 and PD-1 inhibits T cell function by inducing T cell exhaustion to promote immune evasion [17]. Therefore, abnormally upregulated PD-L1 levels in cancer cells and some immune cells results in immune escape. Anti-PD-1/PD-L1 antibodies have become a hot topic in cancer immunotherapy.
PD-1, also known as CD279, is a type I transmembrane protein encoded by the PDCD1 gene of the CD28 immunoglobulin superfamily. It was first discovered and reported by Ishida et al. in 1992 [15, 16]. PD-1 is mainly expressed in activated CD4+ T cells, CD8+ T cells, natural killer T cells, B cells, macrophages, dendritic cells (DCs) and monocytes; its expression is induced by the T or B cell receptor pathway and enhanced by the stimulation of tumor necrosis factor [18]. However, naive T and B cells barely express PD-1 [19,20,21]. PD-1 is comprised of 288 amino acids, including a single Ig variable-type (IgV) extracellular domain, a transmembrane domain and a cytoplasmic domain [22,23,24]. Its extracellular domain is similar to that of other members of the CD28 superfamily, containing an Ig variable-type domain that is important in ligand binding. N-terminal and C-terminal tyrosine residues in the cytoplasmic domain are involved in the formation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs), respectively [16, 24,25,26]; the latter is the main signal transduction domain of PD-1 and is closely related to the response activity of effector T cells.
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