Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a systematic review and meta-analysis

Among the most common cancers worldwide, colorectal cancer ranks third, accounting for 10% of all tumor cases [1]. In 2012, the disease engendered 1,400,000 new cases and nearly 700,000 deaths [2]. According to relevant research, 4.96% of the population born in the USA are suffering from colorectal cancer [3]. Even in Asia, where the incidence rate is reported to be the lowest [4], the threat posed by colorectal cancer cannot be underestimated. Taking China as an example, the incidence and mortality of colorectal cancer there have kept rising. China’s cancer statistics manifest that the incidence and mortality of colorectal cancer ranked fifth among all malignant tumors in China, bringing about 380,000 new cases and 190,000 deaths annually. When they are seeking medical examination, most patients have already been in the advanced stage [5, 6]. Despite the continuous development of treatment technology, the 5-year survival rate of patients with metastatic disease is still less than 10% [7], which is probably due to the inability to diagnose early and the lack of specific markers to determine tumor development or patients’ prognosis. Therefore, to enhance the prognosis of patients with colorectal cancer, it is indispensable to explore effective diagnostic and therapeutic methods.

Programmed cell death protein 1 (PD-1), a sort of inhibitory checkpoint molecule, was discovered and named by Japanese scholar Ishida in 1992 [8]. It belongs to the CD28 family and is expressed on the surface of activated T cells to regulate proliferation and activation [9]. PD-L1 (also known as B7-H1) is the dominant ligand for PD-1 and expressed in activated T cells, B cells, dendritic cells, macrophages, endothelial cells, and a significant number of tumor cells [10]. In the healthy immune system, the activation of the PD-1/PD-L1 pathway can inhibit the immune function of T lymphocytes and promote the inhibitory function of regulatory T cells, which can reduce the immune response of the body to normal peripheral tissues. Consequently, it can inhibit autoimmune responses, prevent the development of autoimmune diseases, and maintain autoimmune tolerance in healthy individuals [11]. When cancer occurs, the tumor cells will reduce their immunogenicity by expressing PD-L1. Hence, they will not be recognized by the immune system and will evade immune attack [12]. In a variety of tumors, the PD-L1 expression is usually associated with poor prognosis [13, 14].

Current theories on the expression of PD-L1 in colorectal cancer and tumor prognosis are limited and controversial. Some studies have manifested the palpable connection between PD-L1 expression and overall survival rate of colorectal cancer patients [15‐18], but the others utter the contradictory statement [19, 20]. So, we used meta-analysis to analyze the prognostic value of programmed death factor ligand 1 (PD-L1), which will also lay a theoretical foundation for the application of PD-1/PD-L1 immunoassay point inhibitors in colorectal cancer.

PD-1 and PD-L1 are inhibitory costimulatory molecules. When tumor cells express PD-L1 to combine with the PD-1 provided by tumor-infiltrating lymphocytes, the immune effect of T cells in the tumorous microenvironment is inhibited, which mediates the occurrence of tumor immune escape and promotes the progress of cancer [25]. At present, a lot of research has been done on this pair of inhibitory costimulatory molecules, but the regulatory mechanism of the signaling pathway in colorectal carcinoma has not been clarified, and theories in many fields are controversial. Although some systematic reviews focused on the prognostic value of PD-L1 in all types of solid tumors also mentioned the relationship between PD-L1 and prognosis of colorectal cancer in passing [26‐28], yet their results in this regard had limitations because of the lack of in-depth research. Wu et al. suggested that PD-L1 overexpression was positively correlated with 5-year OS deterioration in colorectal cancer, but they only included two papers and used OR value to evaluate the results, meaning the existence of great bias [28]. Different from the above conclusion, Pyo et al. applied HR involving PD-L1 to assess the relevance between PD-L1 expression and prognosis of colorectal cancer and then concluded that there was no connection between them. However, they merely contained four retrospective studies, which lacked persuasiveness [27]. Xiang et al. also argued that PD-L1 could not be used as a prognostic indicator of colorectal cancer, but they misapplied risk ratio (RR), a specific measure for evaluating prospective studies, to the analysis of retrospective studies, so the findings should be treated cautiously [26]. Therefore, to resolve the controversy and deficiency mentioned above, this meta-analysis comprehensively collected relevant literature based on the inclusion criteria and adopted the hazard ratio (HR) associated with PD-L1 to estimate the prognostic value of PD-L1 in colorectal cancer. In addition to that, we also explored the relationship between the expression of PD-L1 and the clinicopathological characteristics of colorectal cancer to make the outcome more convincing.

This meta-analysis demonstrated that PD-L1 expression could be utilized as an independent factor in judging the prognosis of colorectal cancer (HR = 1.22, 95%CI = 1.01–1.48, P = 0.04, random effect). Nevertheless, there was inevitable heterogeneity among the retrospective studies included in this meta-analysis (P = 0.0002, I² = 67%). In order to make the conclusion more persuasive and scientific, we adopted the subgroup analysis to explore the heterogeneity sources. And as the findings suggested, the heterogeneity of each subgroup decreased in varying degrees, indicating that these factors have certain degrees of influence. Among them, the non-Asian group had the minimum heterogeneity (I² = 12% < 50%), which implied the essential role the regional or ethnic differences played on engendering heterogeneity.

As the subgroup analysis of PD-L1 and clinicopathological features indicated, PD-L1 overexpression in colorectal cancer cells was associated with lymphatic invasion. Previous experimental studies have shown that they are indeed relevant. Epithelial-to-mesenchymal transition (EMT) leads to lymphatic invasion [29], and the expression of PD-L1 in tumor cells facilitates immunosuppression, both of which contribute to tumor progression and metastasis. MiR-200/Zinc finger E-box-binding homeobox 1 (ZEB1) was initially known as EMT regulatory axis, and the bidirectional negative feedback regulation mechanism between ZEB1 and miR-200 makes the corresponding cells actualize EMT [30]. But recently, the mechanism that miR-200/ZEB1 axis can also regulate PD-L1 to facilitate immunosuppression has been proved by experiments [31]. Therefore, the relationship between lymphatic invasion and PD-L1 overexpression can be considered to be mutually “parallel.” Also, consistent with another inference of this meta-analysis that the inhibition of the PD-1/PD-L1 signaling pathway in advanced colorectal cancer could achieve remarkable results, existing clinical trials have exhibited the high security and activity of the treatment with PD-1/PD-L1 immunocheckpoint inhibitors [32].

To mention first, all the included articles were retrospective studies, whose bias could not be eliminated, so the consequences were generally stable. Also, it should be noted that all the articles included are in English, meaning the lack of research especially those negative studies in non-English speaking countries, which leads to the absence of representativeness and the production of bias.

Secondly, it has been reported that the expression of PD-L1 in tumor cells is a critical factor in making the monoclonal antibody against PD-1/PD-L1 effective. However, in every article, the threshold of PD-L1 positive is different and brings about a tremendous impact on the experimental results. According to published articles, patients with PD-L1 positive can obtain a better outcome in the treatment with immunocheckpoint inhibitors as the threshold increases [33]. So, uniformly applying the most suitable PD-L1 positive threshold to the following research should be a top priority. Besides that, using of different immunohistochemical antibodies in various studies leads to specific errors.

Furthermore, the latest experiments indicate that cancer patients [34] with intestinal flora disorders have a worse prognosis in the treatment with anti-PD-1/PD-L1 antibodies, which can be concluded that intestinal flora balance plays a vital role in the efficacy of PD-1/PD-L1 immunocheckpoint inhibitors. Therefore, the following study in this field should take intestinal flora into consideration.

This study analyzed all the available interrelated information in the published literature and exhibited that the expression of PD-L1 was significantly correlated with the overall survival rate of colorectal cancer. The more the PD-L1 was expressed, the worse prognosis the colorectal cancer patients would undergo. Concerning clinicopathological features, the expression of PD-L1 was bound up with lymphatic invasion and tumor stage, but not gender, microsatellite instability, or tumor differentiation. In other words, the expression of PD-L1 could be utilized as an independent factor in judging the prognosis of colorectal cancer, and patients with advanced cancer or lymphatic invasion were more likely to express PD-L1. This conclusion may lay a theoretical foundation for the application of PD-1/PD-L1 immunoassay point inhibitors but still need to be verified by sizeable well-designed cohort studies.