ABSTRACT
An increasing body of research indicates that immunotherapy has demonstrated substantial effectiveness in the realm of metastatic colorectal cancer(mCRC), especially among patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) (dMMR/MSI-H mCRC). This study constitutes the inaugural bibliometric and visual analysis of immunotherapy related to mCRC during the last decade. Between 2013 and the conclusion of 2022, we screened 306 articles from Web of Science and subjected them to analysis using CiteSpace and VOSviewer. The United States stood out as the primary contributor in this area, representing 33.33% of the publications, with China following closely at 24.51%. The most prolific institution has the lowest average citation rate. Sorbonne University were the most highly cited institutions. Notably, Frontiers In Oncology published the largest quantity of articles. Andre, Thierry, and Overman, Michael J. were prominent authors known for their prolific output and the high citation rates of their work. The focus areas in this field encompass “tumor microenvironment,” “liver metastasis,” “tumor-associated macrophages,” “combination therapy” and “gut microbiota.” Some keywords offer promise as potential biomarkers for evaluating the effectiveness of immunotherapeutic interventions.
Introduction
Colorectal cancer (CRC) is the third most common cancer globally, and its mortality rate raises deep concern, Statistics reveal that CRC claims the lives of over 900,000 individuals annually, with metastatic colorectal cancer bearing a particularly grim prognosis.Citation1 When the condition advances to a late stage, the most significant challenge for patients is the notably low survival rate linked with this disease.Citation2 The management of unresectable mCRC primarily encompasses systemic therapies, such as targeted therapy, chemotherapy, anti-angiogenic therapy, immunotherapy and combination therapies.Citation3
Various forms of immunotherapies have demonstrated substantial effectiveness in clinical practice.Citation4 Supported by compelling evidence from multiple clinical trials,Citation5–7 pembrolizumab, nivolumab and ipilimumab have received FDA approval for the treatment of mCRC. All three exhibit consistent, effective and enduring responses in tumor treatment.
Bibliometric analysis is a quantitative approach employed to study and evaluate academic literature. It effectively identifies emerging trends and alterations in published articles, furnishing valuable insights and evidence to guide decisions regarding future research directions.Citation8 Our study employs bibliometric analysis of the last decade’s literature to consolidate past achievements, steering future research endeavors and advancing the development of immunotherapy for metastatic colorectal cancer.
Materials and method
This study employed the Web of Science (WOS) as the primary database. Web of Science, renowned as a high-quality database, is widely accepted by numerous researchers.Citation9 The WOS Core Collection was systematically searched from early 2013 until the end of 2022, to identify all articles pertaining to mCRC immunotherapy as of October 4, 2023. In advanced search mode, the following search approach was employed: TS=(Metastatic Rectal Cancer* OR Advanced Rectal Tumor* OR Metastatic Colon Neoplasm* OR Advanced Rectum Neoplasm* OR Metastatic Rectum Tumor* Advanced Rectum Tumor* OR Metastatic Rectum Cancer* Advanced Rectum Cancer* OR Metastatic Colon Neoplasm OR Advanced Cancer of Rectum OR Metastatic Colonic Neoplasm* OR Advanced Colon Neoplasm* OR Metastatic Cancer of Colon * OR Advanced Colorectal Tumor* OR Metastatic Colorectal Cancer* OR Advanced Colorectal Cancer* OR Metastatic Colorectal Carcinoma* OR Advanced Colonic Cancer * OR Metastatic Colonic Neoplasm* OR Advanced Colonic Neoplasm* OR Metastatic Rectum Neoplasm* OR Advanced Cancer of Rectum * OR Metastatic Colorectal Tumor OR Advanced Cancer of Colon OR Metastatic Colon Cancer* OR Advanced Colorectal Cancer* OR Metastatic Colorectal Carcinoma *OR Metastatic Rectum Neoplasm* Advanced Rectum Neoplasm* OR Advanced Colorectal Carcinoma) AND TS=(Immunotherapy). The final documents comprise “all records and cited references,” and the screening process is depicted in .
Figure 1. Flowchart illustrating the article selection process.
Our research employed CiteSpace (version advanced 6.2.R5) and VOSviewer (version basic 1.6.19) to generate visual representations of the bibliometric analysis results. Both of these software tools are widely utilized for bibliometric analysis.Citation10 CiteSpace is a robust academic tool that supports researchers in achieving a more profound grasp of the field’s evolution and trends, furnishing essential perspectives and insights for academic research.Citation11 On the other hand, VOSviewer stands out for its user-friendly mapping and visually appealing images, enabling researchers to easily analyze and present complex literature data.Citation12
Results
In the period from 2013 to the end of 2022, this study screened 306 publications on WOS. These publications involved 44 different countries or regions, 707 institutions or organizations, and 2,293 authors. They were published in 139 different journals and collectively cited 10,278 distinct articles from 1,554 journals. Among these, 215 were articles (70.26%), and 91 were reviews (29.74%).
illustrate annual Publications on Immunotherapy in mCRC from 2013 to 2022 and Country-Specific Trends. The United States (USA) leads in terms of publications in this field, contributing 102 papers (33.33%). China closely follows with 75 publications (24.51%) (). Countries with high centrality (>0.1) encompass the USA, Italy, China, the UK, Japan, Spain and Canada (). USA and China lead in publication volume, with their combined publications exceeding 50% of the total, significantly surpassing all other countries. presents the top 10 most prolific institutions. Anderson Cancer Center has published 14 papers and garnered 125 citations. The majority of institutions are either from the United States or Italy. Institutional collaboration network analysis () indicates that institutions with higher publication output tend to engage in more extensive collaboration.
Figure 2. Annual publications on immunotherapy in mCRC from 2013 to 2022 and country-specific trends.
Figure 3. A visual map of countries and institutions associated with mCRC immunotherapy. (a) Country collaboration analysis; (b) Institutional collaboration analysis. The nodes represent countries or institutions, and the lines connect them. Nodes symbolize countries/regions or institutions, while connecting lines signify relationships between them. The size of the nodes is directly proportional to the number of publications associated with each entity. The thickness of the connecting lines reflects the strength of the cooperation between nodes, with thicker lines indicating closer collaborative relationships. The nodes with the outermost purple circles demonstrate higher centrality within the network. From 2013 to 2022, the color changes from brown to green.
Table 1. The top 10 productive countries related to mCRC immunotherapy.
Table 2. Top10 institutions published literature related to mCRC immunotherapy.
present the top ten journals with the highest publication counts and the most co-cited journals, respectively. Frontiers In Oncology boasts the highest publication count with 19 articles (6.21%). Oncoimmunology boasts the highest citation/publication ratio at 43.00. Six journals belong to Q1, and one journal each falls into Q2 and Q3, with two journals are in Q4. According to , Lancet is cited 248 times, and it has the highest Impact Factor, standing at 168.73. All these journals fall into the Q1 category. illustrates the relative alignment of this research topic within the primary research disciplines.Citation13 The utilization of Z-Scores function emphasizes two primary colorful connections, revealing that journals from the fields of biology, molecular and immunology (orange trajectory) and pharmaceuticals, medicine, clinical studies (green trajectory) are notably influenced by journals from biology, molecular and genetics field (z = 2.61, f = 83034).
Figure 4. The dual-map overlay of journals related to mCRC immunotherapy.
Table 3. The top 10 productive journals related to mCRC immunotherapy.
Table 4. The top 10 co-cited journals associated with mCRC immunotherapy.
Examining the authors of the literature can unveil the leading researchers and the central research forces in the field. Lotka’s Law,Citation14 suggests that core authors in this domain should have a minimum of approximately three publications, calculated by m = 0.749*√nmax ≈3(as calculated by VOSviewer with nmax being 7). Thus, core authors are those with three or more publications. First, core authors are visualized based on their respective countries using VOSviewer, as depicted in . Additional analysis of highly productive authors in this field over the last decade is detailed in . Andre, Thierry, who has authored 10 articles, received 1402 citations, and maintained an average citation frequency of 140 times per paper, is the most prolific author in terms of publications. shows a visualization of co-cited authors related to mCRC immunotherapy.
Figure 5. A visual map of authors associated with mCRC immunotherapy.
Figure 6. A visualization of co-cited authors and references related to mCRC immunotherapy. (a) Network visualization diagram of the co-cited authors of the publications. (b) Network visualization diagram of cited references. Nodes represent co-cited authors or cited references. Connecting lines depict co-citation relationships. Node size increases as the number of co-citations rises. Colors denote different years: in A, the color shifts from purple to yellow between 2013 and 2022, and in B, the transition is from blue to yellow over the same time frame.
Table 5. Top 10 most prolific authors in the field of mCRC immunotherapy.
illustrates the co-cited references network, present the top five references with the highest citations and centrality. The article PD-1 Blockade in Tumors with Mismatch-Repair Deficiency authored by Le DT has garnered the greatest number of co-citations, reaching 174.
Table 6. The top five co-cited references related to mCRC immunotherapy.
Table 7. The top five centralities of co-cited references related to mCRC immunotherapy.
We identified keywords that appeared more than 10 times among the initially extracted 122 keywords. Out of these, 67 keywords met the specified threshold. After removing irrelevant keywords, the analysis of keywords citation counts and centrality (refer to ) reveals that the most frequently used keywords were “Microsatellite instability” (appearing 41 times), “Immune checkpoint inhibitors” (appearing 29 times), “Nivolumab” (appearing 24 times), “Pembrolizumab” (appearing 21 times), and “Tumor microenvironment” (appearing 18 times). provides a density visualization of keyword co-occurrence, where node brightness represents occurrence frequency.
Figure 7. Density visualization of the keywords in the publications of immunotherapy in mCRC showing the co-occurrence of keywords, where the size of nodes indicates the frequency of occurrence.
Table 8. The top 5 most frequent and centralized keywords related to mCRC immunotherapy.
Furthermore, we used CiteSpace to create visual representations of keyword timelines (see ) and time zone maps (see ), elucidating the development of these hotspots.Citation15 We observed that, in addition to “advanced rectal cancer” (cluster 0) and “recurrent colorectal cancer” (cluster 1), which are focal points of researchers’ attention, “PD-1 inhibitor” (cluster 2), “microsatellite instability” (cluster 3), “mismatch repair status” (cluster 5), and “tumor infiltrating lymphocytes” (cluster 6) have been key research hotspots in this field since 2013. Additionally, the inclusion of “clinical trials” (cluster 4) suggests that researchers have conducted numerous clinical trials closely aligned with this field.
Figure 8. A timeline(A) and time zone(A) view of keywords for mCRC immunotherapy.
Also, burst keywords () are identified by CiteSpace in this field and gain insights into the evolving research trends. A total of 13 high-burst keywords were identified, including “immune checkpoint inhibitors” (burst strength is 6.15), “CEA” (burst strength is 4.28), “gut microbiota” (burst strength is 3.46), “liver metastasis” and “mismatch repair deficiency” (both with a burst strength of 2.83), “monoclonal antibody” (burst strength of 2.81), “combination therapy” (burst strength is 2.47), “microsatellite stable” (burst strength is 2.4), “adoptive immunotherapy” (burst strength is 2.4).
Figure 9. Burst keywords in articles related to mCRC immunotherapy. A blue line indicates the timeline, and the intervals in which bursts were found are he timeline, and the intervals in which bursts were found are indicated by red sections on the blue timeline, indicating the start year, the end year, and the burst duration.
Discussion
In our study, we retrieved and manually screened 306 publications on immunotherapy for mCRC published between 2013 and 2022. The annual publication count showed a significant increase after 2016, and rapid growth was observed from 2019 onward. USA has consistently been the leading contributor to academic output in the domain of immunotherapy for mCRC during the last ten years. China had fewer annual publications in the years leading up to 2019, but starting in 2021, it exceeded the USA. While the average citation counts per publication is notably lower compared to other countries, the substantial volume of publications also highlights China’s substantial contributions to this field.
Among the top 10 most prolific institutions, 70% are either from USA or Italy. This indicates that academic development in this field is significantly promoted by these two countries. Interestingly, the institution with the highest global productivity also has the lowest average citation rate per article within the top 10 institutions.
According to , it can be deduced that the majority have a focus on clinical medicine and immunology. indicate that research in this field can be categorized into two primary directions. One is centered on fundamental medical research, while the other emphasizes clinical applications.
Thierry Andre from Sorbonne University in France ranks the first position among the top 10 prolific authors. He has authored 10 articles that have received 1402 citations, resulting in an impressive average citation/publication ratio of 140. One of his studies concluded that first-line treatment with pembrolizumab in MSI-H/dMMR mCRC resulted in extended PFS and a reduced incidence of adverse events.Citation5
Based on , one article analyzed the relevance of six independent classification systems for colorectal cancer and combined them into four molecular subtypes with significant characteristics. This work provides a foundation for future clinical stratification and subtype-based precision therapy.Citation16 The other two highly central articles discuss the crucial role of ICIs in cancer immunotherapyCitation17 and their safety and adverse effects.Citation18 They not only establish the theoretical foundation for the future clinical utilization of these drugs but also function as a guide for clinicians, reducing the severity of side effects.
The most frequently appearing and highly central keywords are all related to the mechanisms of tumor immune checkpoint inhibitor against cancer. A study conducted by Nicolas J. Llosa et al.Citation19 investigated the immune distinctions between MSI and MSS CRC. The outcomes revealed that MSI tumors exhibited increased levels of immune infiltration and expressed various inhibitory immune genes within tumor-infiltrating lymphocytes and the stroma. This finding carries significant clinical implications for the identification of MSI patients eligible for ICIs in clinical trials. In addition to dMMR/MSI-H late-stage colorectal cancer patients, Fan A also suggests that the majority of mCRC patients may reap latent benefits from immunotherapy, even in the context of pMMR/MSI-L scenarios.Citation20
The analysis of keyword bursts reveals the evolution of hotspots in the field of mCRC immunotherapy, providing insights into future research trends.Citation21 Although monotherapy for dMMR/MSI-H mCRC shows a significant increase in sustained tumor regression and manageable safety, more than 50% of patients do not benefit from monotherapy.Citation22 Studies have indicated that combined utilization of multiple ICIs may become a future research focus in this field. The CCTG CO.26 study discovered that the use of durvalumab in combination with tremelimumab has showed remarkable effectiveness in extending the overall survival of MSS mCRC patients.Citation22 Owing to the link between resistance to EGFR monoclonal antibodies and increased expression of PD-L1, the combination of these drugs in MSS mCRC treatment not only exhibits promising efficacy but also ensures safety.Citation23 Research suggests that when ICIs are used in combination with bevacizumab(an anti-angiogenic agent), they show remarkable anti-tumor responses in pMMR/MSS/MSI-L mCRC.Citation24 Radiation-induced cell death has the potential to improve antigen presentation, activate T cells and enhance the responsiveness to immunotherapy through peripheral effects.Citation25 The combined treatment of ICIs and radiotherapy demonstrated substantial research potential in a clinical trial.Citation26 Initial findings from preclinical studies suggest that inhibiting the MEK molecule downstream of the RAS-MAPK pathway can raise PD-L1 expression and enhance the effects of ICIs.Citation27 Dual-specificity antibodies can simultaneously target two distinct antigens, linking tumor cells with T cells. The combined treatment of CEA-CD3 and PD-L1 has demonstrated significantly higher anti-tumor effectiveness than monotherapy in MSS mCRC patients.Citation28 Various potential combinations, including those with cancer vaccines,Citation29 oncolytic virusesCitation30 and gut microbiotaCitation31 have shown substantial progress. These promising prospects may offer clinicians novel treatment strategies. To summarize, the combination of immunotherapy, targeted therapy, anti-angiogenic agents, MEK inhibitors, dual-specific antibodies, radiation therapy and various other treatment modalities may enhance the effectiveness of immunotherapy, reinforcing the current dominant research direction of integrating ICIs with other treatment modalities in this field.
Colorectal cancer often spreads to the liver due to the liver’s abundant blood supply and its dual supply from both hepatic artery and portal vein.Citation32 CD8+ T cells are influenced by the portal effect in the context of liver metastasis. Once these CD8+ T cells are activated, they interact with liver macrophages derived from CD11b+ F4/80+ monocytes and expressing FasL. Therefore, this phenomenon causes systemic immune suppression in preclinical models. Additionally, regulatory T cells (Tregs) are implicated in inhibiting other immune cells, while CD11b+ monocytes play an essential role in immune responses. Notably, monotherapy with PD-1 inhibitors cannot reverse this state of immune inhibition.Citation33 Consequently, investigating the resistance mechanisms within the context of CRC liver metastasis and identifying novel-generation immune checkpoints may become a future research priority.
The tumor microenvironment (TME) refers to the cellular milieu surrounding collective tissue and a tumor, encompassing immune cells, vascular endothelial cells, tumor-associated macrophages, secreted factors, extracellular matrix and fibroblasts.Citation34 The TME significantly influences tumor formation, growth, invasion, metastasis, and responses to treatment. It consists of various components that can interact, potentially either promoting or inhibiting tumor progression.Citation35 Fibroblasts are crucial components of TME and can produce fibroblast activation protein (FAP).Citation36 FAP and its secretions can hinder the immune response through diverse mechanisms.Citation37 Some tumors produce vascular endothelial growth factor (VEGF) to meeting tumor’s demands. Nevertheless, the higher levels of angiogenic factor expression have been found to be causally linked to lower T cell infiltration in tumors.Citation38 Macrophages and other myeloid lineage cells are prevalent in the TME, which may lead to immune evasion. Under the influence of specific signaling molecules, M2-type macrophages are induced, differ from M1-type macrophages as they lack cytotoxicity and instead promote immune suppression by producing inhibitory factors.Citation39 Furthermore, they can further reinforce immune suppression through the secretion of CCL22. Immune-suppressive cells within the myeloid lineage inhibit immune responses through mechanisms like arginase expression and nitrosylation of surface protein on infiltrating T cell, thus aiding immune escape.Citation40
A growing body of research indicates a strong association between the gut microbiota and a range of physiological and pathological conditions, including cancer. In 2015, a group of researchers from the United States conducted a study highlighting the potential of Bifidobacterium, a type of gut bacteria, to augment the efficacy of PD-L1 blockade therapy through its impact on adenosine metabolism.Citation31 Specifically, mice treated with Bifidobacterium demonstrated significantly improved anti-tumor effects compared to untreated mice, revealing a synergistic interaction with PD-L1 blockade.Citation41 In the same year, another research endeavor discovered that the absence or depletion of Bacteroides fragilis compromised the therapeutic effectiveness of CTLA-4 inhibition, whereas the introduction of this bacterium resulted in an augmentation of the anti-tumor benefits of CTLA-4 inhibition therapy.Citation42 To conclude, utilizing the modulation of gut microbiota for optimizing the effectiveness of ICIs immunotherapy represents a burgeoning approach.
Immunotherapy has significantly influenced clinical treatment for metastasis colorectal cancer. Nonetheless, there is an urgent demand for research aimed at identifying precise biomarkers capable of predicting immunotherapy’s effectiveness. Keyword analysis identifies four potential biomarkers: “tumor mutation burden,” “tumor-infiltrating lymphocytes,” “expression” and “gut microbiota.” Tumor mutation burden (TMB) quantifies the mutations within tumor cellsCitation43; elevated TMB correlates positively with heightened responsiveness to immunotherapy.Citation44 Tumor-infiltrating lymphocytes (TILs) denote the degree of immune cell infiltration present within tissue. Elevated TIL density is associated with enhanced responses to immunotherapy.Citation45 PD-L1, an immune checkpoint molecule expressed on tumor cells, inhibits immune cell activity. Nevertheless, its accuracy and consistency as a predictive indicator are still under discussion.Citation46 Current research indicates that distinct gut microbiota compositions can modulate immune responses and might govern a tumor’s responsiveness to immune checkpoint inhibitors.Citation31
Conclusion
Our study utilized bibliometric and visual analysis to explore the landscape of immunotherapy in metastatic colorectal cancer over the last decade. Our findings show the significant role played by the United States in advancing immunotherapy for metastatic colorectal cancer. Most research in this domain is published in high-impact journals. Current research in this field focuses on synergistic therapeutic approaches to enhance treatment efficacy. This includes integrating immunotherapeutic agents with immunomodulators, targeted medications, anti-angiogenic factors, MEK inhibitors, and diverse treatment modalities. Future studies are expected to maintain their focus on these aspects, potentially exploring immune evasion mechanisms, scrutinizing the tumor microenvironment intricacies, and identifying predictive biomarkers for therapeutic efficacy.
Author contributions
YG contributed to writing, investigation, and table preparation. MW was involved in the investigation. JK was responsible for figure preparation. M.F., S.S., and L.G.P.H provided supervision and conducted the review.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
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