Unveiling the Research Landscape and Emerging Trends in Cell Cycle for Cancer Immunotherapy: A Bibliometric Analysis (1990–2022)

Background

The cell cycle represents the fundamental biological phenomenon, and its dysregulation is a characteristic of malignant illnesses that significantly affect various tumor behavior aspects. Anti-cell cycle treatment can achieve promising outcomes in several malignant illnesses in different cancers [1]. However, it is still necessary to further understand the cell cycle, particularly the role of tumor immunology [2]. Recent studies have shown that mutations or amplifications of cyclin-dependent kinases (CDK) and its regulators (eg, INK4 and CIP/KIP) lead to abnormal CDK protein expression, thus resulting in abnormal cell proliferation and promoting tumor development [3]. Moreover, further research has discovered that selective CDK inhibitors can promote the arrest of the cancer cell cycle and enhance anti-tumor immunity [4], consistent with the results obtained by Minton, who reported that cell cycle inhibitors boosted tumor immunogenicity [5].

Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for a substantial number of cancer patients. However, only 20–40% of patients derive benefit from these new therapies. PD-L1, an important immunosuppressive molecule, has been utilized as a biomarker for guiding the selection of eligible patients for ICIs therapy [6]. PD-L1 protein level fluctuates in the process of cell cycle progression and modulates its stability protein via cell cycle kinase, indicating that the combination therapy with PD-1/PD-L1 immune checkpoint blockers and CDK inhibitors may be used to improve the clinical outcomes of cancer patients [7,8]. Some studies have indicated that the DNA damage repair-mediated inflammatory signaling pathway, which arrests cell cycle progression, has restricted the efficacy of some tumor immunotherapies [9–13]. Therefore, as the PD-1/PD-L1 pathway is not the sole limiting factor of anti-tumor immunity, it has been validated that combining ICIs with other novel targeted therapies, such as CDK inhibitors, can contribute to superior anti-tumor efficacy [14,15].

At present, numerous excellent articles have been published concerning the applications of cell cycle dysregulation for tumor genesis and development. However, a comprehensive study assessing these relevant publications is lacking about the TME, especially for the role of immunology. Additionally, numerous critical facts are overlooked by researchers because they just explore relevant studies from only 1 or a few perspectives. It remains challenging for investigators to analyze relationships across countries, institutions, and authors, as well as references based on excessive relevant literature. Bibliometrics, a powerful tool that utilizes statistical and mathematical approaches for the quantitative analysis of numerous studies in a specific research field, addresses these problems. Currently, scientometric analysis of relevant studies is mostly conducted using CiteSpace, VOSviewer, and the R package “bibliometrix.” These tools have been used by many researchers for assessing research hotspots, knowledge domain, and frontiers in the relevant topic, based on analysis results.

However, scientometric analysis on data regarding cell cycle mapping in immunology is lacking at present. Consequently, the present work aimed to assess studies associated with use of the cell cycle for cancer immunology applications from 1999 to 2022, to depict the current situation in this field and identify novel research directions.

Material and Methods

DATA EXTRACTION AND SEARCH STRATEGY:

The Web of Science Core Collection (WoSCC) database was comprehensively searched to retrieve articles related to cell cycle and immunology published from 1999 to December 1st, 2022. The search formula below was used, TS= (Neoplasm* OR Tumor* OR Cancer*) AND TS=(cell cycle) AND TS=(immunology* OR immunity*). The collected baseline data and study inclusion criteria were: (1) articles based on the theme of cancer cell cycle for immunology, with available data on authors, titles, abstracts, institutions, journals, country/region, keywords, and references; (2) document types including articles and reviews; and (3) articles written in English. The study exclusion criteria were data papers, book chapters, proceedings papers, meeting abstracts, duplicates, editorials, and unpublished articles with insufficient data. Any disagreement was resolved by consulting a senior physician. The study flowchart is shown in Figure 1. As this study was based solely on the literature, the requirement to obtain informed consent or approval from the institutional review board was waived.

STATISTICAL METHODS:

Relevant data were collected and processed using an automatic algorithm and machine intelligence in the bibliometric software. In this study, the institutions, countries or regions, journals, and keywords of publication traits were collected. Moreover, the H-index, which reflects the scientific research value, was also considered [15]. Our analysis was conducted using the bibliometrix package in R software, which involves various statistical methods, including machine learning theory (see https://www.bibliometrix.org/vignettes/Introduction_to_bibliometrix.html for more details). VOSviewer (1.6.18) and CiteSpace (5.7.R5) were utilized to analyze collaboration networks and identify burst keywords through reference citation analysis.

Results

OVERALL INFORMATION ON PUBLICATIONS:

Altogether, 1844 qualified publications that met the eligibility criteria regarding cell cycle for cancer immunology were identified from the WoSCC database (Figure 2A). In this field, a total of 11 834 authors from around the world participated in the included studies, and the average annual article growth rate was 7.66%. According to our results, this research field is a relatively new one, with an average publication age of 8.21 years (Figure 2B). Importantly, the annual publication number showed an increasing trend over time from 1999, reaching a peak in 2022 (in total, 202 articles were expected to be published). Over the last 10 years, publication numbers regarding this topic rapidly increased, accounting for 65.52% of overall publications. Additionally, the annual mean article citations concerning cancer cell cycle for immunology applications also showed a rapid growth trend (Figure 2C).

ANALYSIS ON COUNTRIES/REGIONS AND INSTITUTIONS:

Altogether, 1844 publications related to the cancer cell cycle for immunology met the eligibility criteria, which were co-authored by 2246 institutions in 51 countries/regions. The international distribution of scientific production according to country in this field are depicted in Figure 3A. Clearly, those 10 most prolific countries who published the most publications are from 4 continents: 4 from Europe (Germany, UK, France, Italy), 3 from Asia (China, Japan, Iran), 2 from North America (the USA, Canada), and 1 from Oceania (Australia). These are all developed countries, with the exception of Iran and China (Figure 3B). The publication numbers arranged by the countries of corresponding authors are displayed in Table 1. Apparently, the USA published the greatest number of publications (36%, 664/1844), while China (19%, 351/1844) and Germany (4.5%, 83/1844) ranked second and third, respectively. Moreover, the USA was the first to investigate the cancer cell cycle for immunology application and had more publications than the other countries (Figure 3C). Among those 10 most prolific countries, the USA was the most prolific and had a higher citation rate, implying the high quality of its publications.

The bibliometric network maps plotted with Bibliometrix displayed the international collaborative relationships between various countries/regions (Figure 4A). As revealed by the maps, the countries/regions with most publications also had the most nodes, suggesting that international collaboration was beneficial for research result output (Figure 4B). However, based on these maps, although the United States and China had the most publications, their collaboration was not as close as that of the European countries.

In terms of institutions, those 10 most prolific institutions regarding the cell cycle for cancer immunology applications are presented in Figure 5A and Table 2. Of them, 7 were in the United States. The University of Montreal was the most prolific institution (n=83), accounting for 1.25% of all publications. Additionally, since the first investigation on cancer cell cycle for immunology applications in 1999, the University of Montreal maintained the highest publication output. By contrast, Johns Hopkins University did not begin research in this field until 2011, but its publication output rapidly increased (Figure 5B). On inter-agency cooperation, the US academic institutions exhibited greater nodes, suggesting the higher degree of institutional cooperation. Furthermore, several research institutions in China (Sun Yat-sen University, Central South University, Shanghai Jiao Tong University, and Fudan University) also exhibited greater nodes, demonstrating their close institutional coordination (Figure 5C). Nonetheless, collaboration between these institutions and those in the USA was lacking.

ANALYSIS OF THE CORE AUTHORS CONTRIBUTING TO PUBLICATIONS:

A total of 11 834 researchers co-authored the 1844 articles related to use of the cell cycle for cancer immunology applications. The results indicate a strong co-occurrence relationship among authors, with authors who have higher productivity often co-occurring more frequently with other authors. According to Lotka’s law on author productivity, most authors authored ≤2 documents, with 88.3% and 96.9% of them authoring 1 and 2 documents, respectively (Figure 6A). In a network map showing relations of author collaboration, large nodes were observed, which suggested the importance of coordination in research result output (Figure 6B). Figure 6C presents the authors’ production over time, where Zhang had the longest timeline, from 2004 to 2020. The top-impact authors measured using H-index are presented in Figure 6D, showing that Wira, Thibault, and Baradaran were the top 3 authors.

INVOLVED JOURNALS AND DOCUMENTS REGARDING THE CANCER CELL CYCLE FOR IMMUNOLOGY APPLICATIONS:

Altogether, 108 academic journals concerning the topic of cancer cell cycle for immunology applications were analyzed. According to our results, the Journal of Immunology was the most prolific (n=262), and Frontiers in Immunology (n=258) and Cancer Immunology Immunotherapy (n=129) ranked second and third, respectively (Figure 7A). Also, among those prolific academic journals, the 3 core sources of academic journals were the Journal of Immunology, Frontiers in Immunology, and Cancer Immunology Immunotherapy (Figure 7B). Figure 7C displays the top 10 journals with greatest H-index impact, with Journal of Immunology (h-index=64) ranking first, followed by Cancer Immunology Immunotherapy (h-index=34) and Nature Immunology (h-index=34). The network map in Figure 7D shows 2 main clusters of academic journals, with diverse journals exhibiting positive citation relations. Additionally, sources with the highest local citations were explored. Table 3 displays the 10 most locally cited journals and Table 4 displays the most globally cited documents.

KEYWORDS DEVELOPMENT OF CELL CYCLE FOR CANCER IMMUNOLOGY APPLICATIONS:

The keyword co-occurrence analysis was conducted on 1844 articles related to cancer cell cycle and immunology applications, and the top relevant keywords were identified (Table 5). These keywords are presented as a bar diagram and a word cloud (Figure 8A). Further, a tree map of the top keywords was created to visualize their frequency of occurrence (Figure 8B). Thereafter, clustering analysis of the keywords was conducted, as represented by different colors in Figure 8C, with thicker inter-node lines indicating stronger associations between the keywords. In addition, trend analysis of the top keywords revealed that the research focus shifted over time. The current research hotspots in this field are “tumor progression”, “chemotherapy”, “resistance”, “clinical trial”, and “target population” (Figure 8D).

Discussion

COUNTRIES/REGIONS, INSTITUTIONS AND INSTITUTION COOPERATION:

The United States, China, and Germany published the most studies, accounting for over half (59.5%) of the published articles. The top 10 countries are from 4 continents, with China and Iran being the only developing countries. The United States (36%, 664/1844) was the most prolific. While there was close coordination among institutions and countries, stronger coordination was observed between the United States and other countries compared with that among countries outside the United States. The distribution of institutions conformed to that of countries, suggesting the importance of international cooperation.

Those 10 most prolific countries are from 4 continents, including 4 from Europe (Germany, the UK, France, Italy), 3 from Asia (China, Japan, Iran), 2 from North America (the USA, Canada), and 1 from Oceania (Australia). These countries are developed countries with the exception of Iran and China. Two of those 10 institutions were from China, while the other 8 were from the United States. However, there was no much international coordination between Chinese and US institutions in the field. Therefore, more close collaboration in cell cycle research for immunology applications is needed to promote advancements in the topic. Additionally, an obvious gap between developed and developing countries exists, which indicates that developing countries may put additional investments in the field and search for close coordination with developed countries.

AUTHORS AND CITED AUTHORS:

Those 3 most active authors were Baradaran, Wira, and Wang, who collectively published at least 17 articles. These 3 authors had a significant impact on cell cycle and immunology research, and made tremendous contributions to research in this field. With regard to H-index, Wira ranked first, followed by Thibault, Baradaran, Wang, and Zhang. Baradaran, from Tabriz University of Medical Sciences, ranked the first among all the co-cited authors. His research on micro-RNA integrated issues of gene expression, oncology, bioinformatics, disease, and cell cycle. Moreover, his biological studies span a wide range of topics, including receptor and blockade, while his recent cancer study combined topics in areas such as genetics and immunology, demonstrating the breadth of his expertise in the field.

JOURNALS AND CITED JOURNALS:

Out of 360 academic journals, 3 core sources-related journals – Journal of Immunology, Frontiers in Immunology, and Cancer Immunology Immunotherapy – were noteworthy, indicating that these journals had a particular interest in studies on use of the cell cycle for immunology applications. Additionally, the top 10 H-index impact rankings were led by the Journal of Immunology (H-index=64), followed by Cancer Immunology Immunotherapy (H-index=34) and Nature Immunology (H-index=34). There were 2 main clusters of academic journals identified, and diverse journals exhibited positive citation relations. Such data may help scientists select the most appropriate journals for submitting research on the cell cycle and immunology.

KEYWORDS:

In bibliometrics analysis, keywords are responsible for summarizing the core contents and research topics. Keyword bursts also indicate the research hotspots in the academic field, while time zone maps help exhibit novel hotspot evolution through keyword analysis [32,33]. Meanwhile, keyword co-occurrence analysis is applied in understanding research hotspot development and distribution in a specific field. Notably, research on cell cycle dysregulation in the early stage mainly focused on tumor proliferation, cell cycle, and apoptosis [34]. Understanding the immune status in TME can offer important data for dynamically monitoring immune responses and exploring combination therapy to provide survival benefits to more patients [35]. Therefore, subsequent research has shifted towards combining cell cycle checkpoint inhibitors and immunotherapy with a focus on anti-tumor metastasis, indicating more emphasizing on their clinical use [25–28,36–39]. Thus, the hotspots of keywords have recently shifted to “pembrolizumab”, “open-label”, “PD-1 blockade”, “blockade”, “invasion”, “migration”, “metastasis”, “target”, “resistance”, and “chemotherapy”.

Over the past decade, targeting PD-1 and PD-L1 has led to a new era in clinical cancer treatment. Nevertheless, the insufficiency in motivating efficient anticancer immunity through suppressing the PD-1/PD-L1 axis remains a problem to be resolved. It has been validated that cell cycle checkpoint combination treatments promote several process during the cancer immunity cycle, eliminate immunosuppressive brakes, and orchestrate the immune-supportive TME [40]. Together with multiple tumor models treatments, this reveals that the combination of PD-1, PD-L1, cytotoxic T lymphocyte–associated protein 4 (CTLA4) antibodies, or other immune checkpoint inhibitors with cell cycle-targeted therapy shows synergistic effects [41–45],which may become the new treatment strategies for clinical application.

Regarding mechanisms, cell cycle checkpoints have been suggested to be important for the activation of cGAS-STING-induced intrinsic immunity and anticancer immunity [41,42,46]. These studies demonstrate that pattern recognition receptors cGAS and STING levels are suppressed for evading immune surveillance [11,35,36]. Additionally, nuclear PD-L1 (nPD-L1) was also discovered to promote cell cycle progression independent of immunity within BRAF V600E-mutated colorectal cancer, which is not responsive to programmed cell death protein 1 (PD-1)/PD-L1 targeting immunotherapy [47]. Moreover, alterations in the DNA damage response pathway during the cell cycle have been identified as a biomarker and anti-tumor immunotherapeutic target [48]. According to Chen, G2/M checkpoint adaptation linked inflammatory pathway activation to anticancer immunity following DNA damage, thereby enhancing immune infiltration as well as anticancer immunity [11]. Furthermore, the keyword trends in research indicate that cell cycle division is becoming increasingly important for anti-tumor immunity.

Our research also has some limitations. Firstly, we only included data from WoSCC and excluded data from other public databases like PubMed, Embase, and Ovid, which may limit the representativeness of our findings. Secondly, only English-language articles were included, which may have introduced linguistic biases. Thirdly, high-quality studies with low citation rates may not have been included, leading to potential bias. Lastly, not all studies published in 2022 were included, and new data may potentially affect our final conclusions.

Conclusions

In conclusion, this scientometric and visual analysis provides a novel perspective on the current situation, development textures, research hotspots, and future directions of use of the cell cycle in cancer immunology research. By analyzing massive unstructured data in a stringent manner provided by computer statistics, our work empowers scholars interested in the cell cycle and immunotherapy to better understand the global research status and future development directions of this domain.