Mapping the intellectual structure and landscape of colorectal cancer immunotherapy: A bibliometric analysis

ABSTRACT

Immunotherapy, particularly immune checkpoint inhibitor (ICIs) therapy, stands as an innovative therapeutic approach currently garnering substantial attention in cancer treatment. It has become a focal point of numerous studies, showcasing significant potential in treating malignancies, including lung cancer and melanoma. The objective of this research is to analyze publications regarding immunotherapy for colorectal cancer (CRC), investigating their attributes and identifying the current areas of interest and cutting-edge advancements. We took into account the publications from 2002 to 2022 included in the Web of Science Core Collection. Bibliometric analysis and visualization were conducted using CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel. The quantity of publications associated with this domain has been steadily rising over the years, encompassing 3753 articles and 1498 reviews originating from 573 countries and regions, involving 19,166 institutions, 1011 journals, and 32,301 authors. In this field, China, the United States, and Italy are the main countries that come forward for publishing. The journal with the greatest impact factor is CA-A Cancer Journal for Clinicians. Romain Cohen leads in the number of publications, while Le Dt stands out as the most influential author. The immune microenvironment and immune infiltration are emerging as key hotspots and future research directions in this domain. This research carries out an extensive bibliometric examination of immunotherapy for colorectal cancer, aiding researchers in understanding current focal points, investigating possible avenues for research, and recognizing forthcoming development trends.

KEYWORDS:

• Colorectal cancer
• immunotherapy
• bibliometric study
• research trends
• VOSviewer
• CiteSpace

Introduction

Globally, colorectal cancer (CRC) is the second highest cause of cancer-related deaths and ranks third in terms of frequently diagnosed cancers.¹ By 2035, it is projected that the number of new cases of CRC worldwide will rise to 2.5 million.² Although screening has advantages in decreasing illness and death rates, about 25% of CRC patients are diagnosed with advanced disease, and roughly 25% to 50% of those with early-stage illness experience the spread of cancer.^3,4 Individuals diagnosed with metastatic colorectal cancer (mCRC) experience a bleak outlook, as their 5-year survival rate are below 15%.² Conventional treatments yield unsatisfactory results due to the occurrence of metastases. Therefore, colorectal cancer currently constitutes a significant disease burden and a public health problem, highlighting the urgent need for the development of new treatments to improve survival rates.

Immunotherapy, as a novel therapeutic approach for treating tumors, has progressed in stages, with immune checkpoint inhibitors (ICIs) emerging as a vital therapy and a central focus of research. In the tumor microenvironment (TME), immune-suppressing tumor signals are blocked by monoclonal antibodies of ICIs. And it can target immune checkpoint proteins like cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1). This action restores the anti-tumor immune response.⁵ Consequently, ICIs have been employed in colorectal cancer treatment, yet response rates and clinical benefits remain suboptimal for most patients. Notably, Le et al. observed a considerably greater response rate to the anti-PD-1 drug pembrolizumab in patients with DNA mismatch repair defective (dMMR)/microsatellite instability-high (MSI-H) molecular type of CRC, suggesting potential benefits for patients with both CRC and non-CRC dMMR tumors from anti-PD-1 therapy.⁶ Nevertheless, approximately 95% of patients with metastatic colorectal cancer (mCRC) fall into the molecular types of mismatch-repair-proficient (pMMR), microsatellite-stable (MSS), or low microsatellite instability (MSI-L).These types exhibit a low mutational load, low neoantigen counts, and reduced immune cell infiltration compared to dMMR-MSI-H mCRC, resulting in diminished immune response and clinical benefits to ICIs.⁷ Therefore, numerous investigators have endeavored to reverse the predicament faced by CRC patients with pMMR/MSS/MSI-L subtypes, who inherently exhibit resistance to ICIs therapy. In addition, the third lymphoid structure (TLS) is an important part of predicting response to ICIs in colorectal cancer. It is an ectopic lymphoid structure located in non-lymphoid tissues and often occurs in autoimmune diseases, chronic infections and cancers.⁸ Recent studies have shown that TLSs and B-cell infiltration in the biopsies of patients with melanoma and renal cell carcinoma correlate with the efficacy of ICIs therapy.⁹ In colorectal cancer, studies have demonstrated that TLSs with different cellular compositions and spatial distributions affect patient prognosis and immune response.¹⁰ However, the specific mechanism of TLSs in the treatment of colorectal cancer with ICIs is not clear, and further studies are needed. In summary, immunotherapy, constituting a vital facet of CRC research and a promising therapeutic approach, is poised to garner increased attention and find broader applications in the future.

Numerous studies on CRC immunotherapy have been published over the past few decades. Nevertheless, to date, few studies have systematically summarized the studies conducted in this domain during the previous two decades, impeding a comprehensive analysis of the progression and prospective path of CRC immunotherapy. Bibliometrics, utilizing mathematical and statistical methods, enables the analysis of information from published papers, providing researchers with a rapid and clear understanding of various aspects of the field and research trends.¹¹ Currently, CiteSpace¹² and VOSviewer^13,14 are the main instruments utilized for the scientometric analysis of literature. Many researchers have adopted this strategy to evaluate their respective research areas.

This study evaluates the literature regarding immunotherapy for CRC over the past 20 y, with the intention of analyzing research hotspots and predicting future directions in this field.

Methods

Data source and search strategy

The data utilized in this research was acquired from the Web of Science Core Collection database (WoSCC), which is widely employed and recognized as an authoritative database for bibliometric analysis. In order to prevent bias caused by regular updates to the database, all publications regarding immunotherapy for colorectal cancer from 2002 to 2022 were obtained and downloaded on August 24, 2023 for further analysis. The search strategy utilized the following terms: TS=(“Rectal Neoplasm” OR “Rectal Tumor” OR “Rectal Cancer” OR “Rectum Neoplasm” OR “Rectum Cancer” OR “Cancer of the Rectum” OR “Cancer of Rectum” OR “Colorectal Neoplasm” OR “Colorectal Tumor” OR “Colorectal Cancer” OR “Colorectal Carcinoma” OR “Colonic Neoplasm” OR “Colon Neoplasm” OR “Cancer of Colon” OR “Colon Cancer” OR “Cancer of the Colon” OR “Colonic Cancer” OR “CRC”) AND TS=(“Immunotherapies” OR “immunotherapy” OR “immune therapy” OR “immunization t.” OR “immunity therapy” OR “immunization therapy” OR “immunotherapy treatment” OR “immunological therapy”). Following the completion of the search, we subsequently filtered out non-original research and review papers, ultimately only research papers and review articles with English-language were considered in this study. The specific screening flow as shown in Figure 1.

Figure 1. Flow chart for search strategy of publications.

Data analysis

Currently, scholars have developed various bibliometric analysis and visualization tools. In this study, we will conduct quantitative, quality, and comprehensive analyses of the current development and research structure of immunotherapy for colorectal cancer. Additionally, we will visualize the results based on these analyses.

Quantitative analysis

The gathered literature was analyzed based on four criteria: the quantity of publications written by the top 10 authors, the quantity of publications in the top 10 journals, the quantity of publications from the leading 10 institutions, and the quantity of publications originating from the top 10 countries/regions.

Quality analysis

The quality analysis was based on the following aspects: authors and co-cited authors, journals and co-cited academic journals, analysis of co-cited references, and analysis of co-cited keywords.

Comprehensive analysis

Our analysis includes visualization and analysis of the cooperative network connections between various countries, the H-index ratings of the leading 10 journals and authors, and the present condition of research in the domain during the previous two decades. Furthermore, we also emphasize future development trends in the field.

Visualization analysis

For visual analysis, the valid data extracted from the WoSCC database were imported into CiteSpace [version 6.1] and VOSviewer [version 1.6.18]. CiteSpace was utilized for analyzing the most intense citation bursts of references and keywords, exploring the current state, focal points, and trends of research, generating temporal distribution maps, and identifying the field’s development trends. VOSviewer was utilized to conduct a visual analysis of the collaborative networks existing among nations, organizations, journals, and authors, as well as the co-citation of clusters of keywords. At the same time, R (version 4.1) enabled the visual analysis of data, which involved connections between authors, institutions, and collaborations among countries on the bibliometric analysis website (http://127.0.0.1:6491/).

By analyzing the frequency of keywords, the centrality degree, and prominence, it is attainable to achieve a thorough comprehension of the current research status, popular areas of interest, and emerging trends in this domain. A network of co-occurrence keywords was built by connecting co-occurrence keywords, where each keyword is represented as a node. In the network, two keywords appearing together in an article is depicted as an edge to indicate their co-occurrence relationship. Nodes with high mean values represent particular subjects that significantly contribute to this field. The degree of occurrence shows the crosstalk and the quantity of co-references of a node, illustrating a gradual rise over time. A higher frequency of appearance indicates a node as a focal point of research in a particular timeframe. If specific parameters and criteria for data selection and analysis are required, please feel free to reach out to the corresponding author.

Results

Annual trends in publications

Based on the specified search criteria and time span settings, 5251 publications related to immunotherapy in CRC were retrieved from the WoSCC database. These comprised 3753 articles (71.47%) and 1498 reviews (28.52%) (Figure 1). Figure 2 illustrates publication trends over the past 20 y, revealing a significant increase in the annual number of publications in this area since 2016.In comparison to the period before 2016, the annual number of publications after 2016 consistently exceeds 200 per year, reaching its peak in 2022 (n = 1,050).Upon data fitting, a high correlation between the year of publication and the annual number of publications is observed (R2 = 0.8771) (Figure 2).

Figure 2. The annual growth trends of publication during the period 2002–2022.

Analysis of countries and institutional

Based on the publication numbers, the distribution of publications among countries is presented in Figure 3(a). Figure 3(c) and Table 1 display the top five countries with the most publications: the People’s Republic of China (1,653 papers), the USA (1,536 papers), Italy (375 papers), Japan (361 papers), and Germany (350 papers). It is worth mentioning that the publication volume is primarily contributed by countries located in Asia, North America, and Europe. Figure 3(b) demonstrates the cooperation among nations, where the red lines represent collaboration between two countries. Of particular interest is the collaboration pattern of the USA, the country with the second-largest number of publications, demonstrating a high level of cooperation with China, Japan, and several European countries. Moreover, the top 10 institutions with the highest quantity of publications are evenly distributed between the USA and China. Sun Yat-sen University leads the list (n = 119), followed by Shanghai Jiao Tong University (n = 97) and the National Cancer Institute (NCI) (n = 88) (Figure 3(d) and Table 2).

Figure 3. (a) Country/region number of publications. (b) Worldwide visualization map of publication collaborations. (c) Cooperation network among top 20 countries/regions based on quantity of publications. (d) Visualization of institutions with publications concerning colorectal cancer immunotherapy.

Table 1. Top 20 active countries/regions.

Rank	Country/Regions	Count	Centrality	Rank	Country/Regions	Count	Centrality
1	CHINA	1653	0	11	CANADA	132	0
2	USA	1536	0.15	12	AUSTRALIA	118	0.12
3	ITALY	375	0	13	SWITZERLAND	102	0.25
4	JAPAN	361	0	14	IRAN	92	0.07
5	GERMANY	350	0.09	15	SWEDEN	86	0.25
6	ENGLAND	254	0.56	16	INDIA	75	0.32
7	FRANCE	229	0.46	17	BELGIUM	71	0.13
8	SOUTH KOREA	159	0.04	18	TAIWAN	70	0.04
9	NETHERLANDS	156	0.04	19	POLAND	69	0
10	SPAIN	151	1.09	20	AUSTRIA	60	0.91

Table 2. Top 20 active institutions.

Rank	Institution	Home country	Count	Centrality	Rank	Institution	Home country	Count	Centrality
1	Sun Yat Sen Univ	China	119	0.01	11	Chinese Acad Sci	China	65	0.05
2	Shanghai Jiao Tong Univ	China	97	0.02	12	Sichuan Univ	China	62	0.02
3	NCI	USA	88	0.07	13	German Canc Res Ctr	German	61	0.11
4	Univ Texas MD Anderson Canc Ctr	USA	87	0.03	14	Huazhong Univ Sci & Technol	China	58	0.06
5	Fudan Univ	China	85	0	15	Johns Hopkins Univ	USA	57	0.1
6	Mem Sloan Kettering Canc Ctr	USA	84	0.3	16	Nanjing Med Univ	China	55	0.03
7	Harvard Med Sch	USA	77	0	17	Peking Univ	China	55	0.01
8	Zhejiang Univ	China	77	0.02	18	Leiden Univ	Netherlands	52	0.16
9	Zhengzhou Univ	China	76	0.02	19	China Med Univ	China	48	0
10	Univ Pittsburgh	USA	66	0.23	20	Duke Univ	USA	47	0.1

Authors and co-cited authors

Over the past two decades, a grand total of 32,301 researchers have made valuable contributions to the realm of immunotherapy for colorectal cancer. Table 3 shows that the top three authors with the most publications were Cohen Romain (n = 15), Andre Thierry (n = 15), and Kopetz Scott (n = 13). Figure 4(a) depicts a network diagram of authors engaged in immunotherapy for CRC, generated using VOSviewer to explore collaboration relationships among authors. In the list of top 10 co-citation authors, Le Dt (n = 1113) secured the top position, followed by Galon J (n = 655), and Siegel RL (n = 615) (Table 3). Author citation relationships were analyzed using CiteSpace, visualizing the network on the web. Co-citation, denoting the simultaneous citation of two studies in a subsequent work, is illustrated in Figure 4(b).

Figure 4. Visualization analysis of author collaborations (a) and author co-citations (b) generated by VOSviewer. Co-occurrence network diagram of journals (c) and co-cited network diagram of journals (d) generated by VOSviewer.

Table 3. Top 10 authors in terms of the number of publications and top 10 authors in terms of total citations.

Rank	Author	Count	Rank	Co-cited Author	Count
1	Cohen, Romain	15	1	Le Dt	1113
2	Andre, Thierry	15	2	Galon J	655
3	Kopetz, Scott	13	3	Siegel RL	615
4	Snook, Adam E	13	4	Overman MJ	614
5	Liu, Zaoqu	11	5	Topalian SL	578
6	Halama, Niels	11	6	Pages F	441
7	Itoh, K	10	7	Rosenberg SA	420
8	Overman, Michael J	10	8	Brahmer JR	362
9	Han, Xinwei	10	9	Sharma P	358
10	Wang, Xin	10	10	Hanahan D	354

Journals and co-cited academic journals

A total of 1011 academic journals have published articles related to colorectal cancer immunotherapy. Frontiers in Immunology (230 papers, IF 2022 = 7.3) takes the lead, closely followed by Cancers (172 papers, IF 2022 = 5.2) (Figure 4(c)). Table 4 presents the top 10 journals based on the number of publications. The Ca-a Cancer Journal for Clinicians from the United States emerged as the journal with the highest impact factor in 2022.The visualization network of co-cited journals is shown in Figure 4(d), demonstrating the influence of each journal on the field’s development.

Table 4. Top 10 journals in terms of the number of published papers.

Rank	Journal	Count
1	Frontiers in Immunology	230
2	Cancers	172
3	Frontiers in Oncology	134
6	Cancer Immunology, Immunotherapy	128
5	Journal for ImmunoTherapy of Cancer	107
7	OncoImmunology	103
4	Clinical Cancer Research	101
9	International Journal of Molecular Sciences	70
8	Cancer Research	63
10	International Journal of Cancer	63

Analysis of co-cited references

Table 5 presents a summary of the 10 most frequently co-cited publications, while Figure 5(a) visually represents these co-cited literatures. One of these is the publication titled “PD-1 Blockade in Tumors with Mismatch-Repair Deficiency” authored by Le Dt et al. with the highest quantity of co-citations (n = 499).⁶ Moreover, 9 of these 10 highly cited publications had an impact factor exceeding 45, and nine of these papers were authored by individuals from the USA, emphasizing the high quality of contributions from the USA in this field.

Figure 5. The co-citation network of literature (a) and labels clustering of co-cited literature based on LLR algorithm (b) generated by CiteSpace.

Table 5. Top 10 cited publications.

Rank	Co-cited reference	Total Citations	Centrality	Journal	Type	IF (2022)	Corresponding author’s country
1	PD-1 Blockade in Tumors with Mismatch-Repair Deficiency	499	0.1	New England Journal of Medicine	Clinical Trial	158.5	USA
2	Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade	455	0.02	Science	Clinical Trial	56.9	USA
3	Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study	452	0.02	Lancet Oncology	Clinical Trial	51.1	France
4	Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer	351	0.03	Journal of Clinical Oncology	Original Research	45.3	USA
5	Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries	287	0	Ca-a Cancer Journal For Clinicians	Original Research	254.7	USA
6	Colorectal cancer statistics, 2020	260	0.01	Ca-a Cancer Journal For Clinicians	Multicenter Study	254.7	USA
7	Immunotherapy in colorectal cancer: rationale, challenges and potentia	241	0.01	Nature Reviews Gastroenterology & Hepatology	Review	65.1	USA
8	Cancer statistics, 2019	217	0	Ca-a Cancer Journal For Clinicians	Multicenter Study	254.7	USA
9	The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints	200	0.04	Cancer Discovery	Original Research	28.2	USA
10	Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer	195	0	New England Journal of Medicine	Randomized Controlled Trial	158.5	USA

The automatic labeling technique of the CiteSpace clustering function was utilized to label the clusters in the literature’s co-citation network. Data visualization using timeline analysis is an analytical method that combines temporal distribution with clustering. The set of cluster references is represented by a straight line at the same horizontal position in Figure 5(b). Nodes of varying colors indicate different years, while the cluster labels are positioned on the right side. The top three clusters are designated as #0 T-cell Infiltration, #1 Mutational Burden, and #2 Clinical Result.

In Table 6, it presents the most frequently cited references, with the initial citation surge observed in 2005. Among these, the reference “Le DT, 2015, NEW ENGL J MED, V372, P2509, DOI 10.1056/NEJMoa1500596” (2016–2020, strength 132.35) exhibits the strongest citation explosion.

Table 6. Top 25 references with the strongest citation bursts.

References		Year	Strength	Begin	End	2002 – 2022
Hurwitz H, 2004, NEW ENGL J MED, V350, P2335, DOI 10.1056/NEJMoa032691		2004	23.3	2005	2009	▂▂▂▃▃▃▃▃▂▂▂▂▂▂▂▂▂▂▂▂▂
Galon J, 2006, SCIENCE, V313, P1960, DOI 10.1126/science.1129139		2006	34.79	2007	2011	▂▂▂▂▂▃▃▃▃▃▂▂▂▂▂▂▂▂▂▂▂
Hodi FS, 2010, NEW ENGL J MED, V363, P711, DOI 10.1056/NEJMoa1003466		2010	40.01	2011	2015	▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂▂▂▂▂▂
Kantoff PW, 2010, NEW ENGL J MED, V363, P411, DOI 10.1056/NEJMoa1001294		2010	27.92	2011	2015	▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂▂▂▂▂▂
Hanahan D, 2011, CELL, V144, P646, DOI 10.1016/j.cell.2011.02.013		2011	22.54	2011	2016	▂▂▂▂▂▂▂▂▂▃▃▃▃▃▃▂▂▂▂▂▂
Brahmer JR, 2012, NEW ENGL J MED, V366, P2455, DOI 10.1056/NEJMoa1200694		2012	44.41	2012	2017	▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▃▂▂▂▂▂
Topalian SL, 2012, NEW ENGL J MED, V366, P2443, DOI 10.1056/NEJMoa1200690		2012	64.9	2013	2017	▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂▂▂▂
Fridman WH, 2012, NAT REV CANCER, V12, P298, DOI 10.1038/nrc3245		2012	32.64	2013	2017	▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂▂▂▂
Pardoll DM, 2012, NAT REV CANCER, V12, P252, DOI 10.1038/nrc3239		2012	45.17	2014	2017	▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▂▂▂▂▂
Wolchok JD, 2013, NEW ENGL J MED, V369, P122, DOI 10.1056/NEJMoa1302369		2013	25.12	2014	2018	▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂▂▂
Llosa NJ, 2015, CANCER DISCOV, V5, P43, DOI 10.1158/2159–8290.CD-14-0863		2015	49.8	2015	2020	▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▃▂▂
Tumeh PC, 2014, NATURE, V515, P568, DOI 10.1038/nature13954		2014	29.93	2015	2019	▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂▂
Snyder A, 2014, NEW ENGL J MED, V371, P2189, DOI 10.1056/NEJMoa1406498		2014	29.53	2015	2019	▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂▂
Herbst RS, 2014, NATURE, V515, P563, DOI 10.1038/nature14011		2014	27.95	2015	2019	▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂▂
Taube JM, 2014, CLIN CANCER RES, V20, P5064, DOI 10.1158/1078–0432.CCR-13-3271		2014	23.61	2015	2019	▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂▂
Muzny DM, 2012, NATURE, V487, P330, DOI 10.1038/nature11252		2012	22.67	2015	2017	▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▂▂▂▂▂
Le DT, 2015, NEW ENGL J MED, V372, P2509, DOI 10.1056/NEJMoa1500596		2015	132.35	2016	2020	▂▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂
Rizvi NA, 2015, SCIENCE, V348, P124, DOI 10.1126/science.aaa1348		2015	34.59	2016	2020	▂▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂
Larkin J, 2015, NEW ENGL J MED, V373, P23, DOI 10.1056/NEJMoa1504030		2015	30.5	2016	2019	▂▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▂▂▂
Borghaei H, 2015, NEW ENGL J MED, V373, P1627, DOI 10.1056/NEJMoa1507643		2015	27	2016	2020	▂▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂
Schumacher TN, 2015, SCIENCE, V348, P69, DOI 10.1126/science.aaa4971		2015	24.58	2016	2020	▂▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▃▂▂
Motzer RJ, 2015, NEW ENGL J MED, V373, P1803, DOI 10.1056/NEJMoa1510665		2015	22.75	2016	2019	▂▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▂▂▂
Guinney J, 2015, NAT MED, V21, P1350, DOI 10.1038/nm.3967	2015		42.36	2017	2020	▂▂▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▂▂
Vetizou M, 2015, SCIENCE, V350, P1079, DOI 10.1126/science.aad1329	2015		24.66	2017	2020	▂▂▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▂▂
Sivan A, 2015, SCIENCE, V350, P1084, DOI 10.1126/science.aac4255	2015		24.35	2017	2020	▂▂▂▂▂▂▂▂▂▂▂▂▂▂▂▃▃▃▃▂▂

Analysis of co-cited keywords

Using CiteSpace, we extracted and examined the keywords from a total of 5,251 publications. These keywords were then presented in the form of network graphs showing their co-occurrence, timeline graphs illustrating their usage over time, and a compilation of the top 25 keywords with the greatest citation intensity. As depicted in Table 7, the top three most frequently used keywords were colorectal cancer (2498 occurrences), immunotherapy (1094 occurrences), and expression (938 occurrences). After eliminating the keywords employed for retrieval, we constructed the network graph of keyword co-occurrence and presented it in Figure 6(a). The keyword timeline plot exposes 11 clusters, with the foremost three clusters denoted as #0 T cells, #1 pathway, and #2 NK cells (Figure 6(b)). Figure 6(c) delineates keywords exhibiting a substantial citation explosion, revealing that immune response (2002–2014, strength 48.25), active specific immunotherapy (2002–2016, strength 34.91), and monoclonal antibody (2002–2011, strength 33.64) attained peak citation intensity during their respective time periods.

Figure 6. Co-occurrence network graph (a) and clustering timeline graph (b) of keyword generated by CiteSpace. (c) Top 25 most cited keywords.

Table 7. Top 20 most frequent keywords analyzed using CiteSpace.

Rank	Keywords	Count	Centrality	Rank	Keywords	Count	Centrality
1	Colorectal cancer	2498	0	11	TUMOR	386	0.02
2	Immunotherapy	1094	0	12	Tumor microenvironment	386	0
3	Expression	938	0	13	Breast cancer	337	0.01
4	Colon cancer	862	0.01	14	Regulatory t cell	312	0.01
5	T cell	586	0.02	15	Cancer	311	0.05
6	Dendritic cell	533	0	16	Carcinoma	311	0.02
7	Microsatellite instability	523	0.01	17	Chemotherapy	295	0.08
8	Cell	445	0.04	18	Blockade	281	0.09
9	Therapy	428	0.01	19	Open label	268	0.03
10	Survival	402	0.02	20	Cancer immunotherapy	263	0.02

Top 10 journals with the greatest H-index scores

The H-Index, introduced by George Hirsch in 2005,¹⁵ is a commonly used measure to assess the overall influence, importance, and scope of a researcher’s cumulative contributions. It represents the number ‘H’ which indicates that ‘H’ papers of the researcher have received citations of at least ‘H’ times, whereas the rest of the papers have been cited less than ‘H’ times. This index, serving as an indicator of the academic standing of journals, considers both the number of publications and the frequency of citations. The H-index was used in our research to evaluate the leading journals that publish articles on immunotherapy for colorectal cancer research.As illustrated in Figure 7(a), CLINICAL CANCER RESEARCH secured the top position with the greatest H-index (H = 53), followed by CANCER IMMUNOLOGY IMMUNOTHERAPY (H = 41) and CANCER RESEARCH (H = 36).

Figure 7. (a) Top 10 published journals ranked by H-index. (b) Top 10 authors ranked by H-index. The research trend quadrant chart (c) and research theme trend map (d) based on keyword.

Top 10 authors with the greatest H-index scores

The H-Index evaluates the significance, importance, and overall influence of a researcher’s cumulative research contributions, considering both the quantity of publications and the number of citations received for those publications. In Figure 7(b), LI Y and ZHANG Y attained the greatest H-index (H = 22), with WANG Y following closely with an H-index of 20.

Research trends over the last two decades

We utilize the bibliometric package in R for visualization analysis to perform a comprehensive examination of trending subjects through keyword analysis. Thematic analysis encompasses keyword clusters and interconnections of authors to discern thematic patterns. This pattern categorizes the keywords into four quadrants based on their density (degree of development) and centrality (degree of relevance) (Figure 7(c)). Centrality signifies the degree of correlation among different subjects, whereas density gauges the coherence among nodes. Both of these factors enable an assessment of the extent and significance of the development of a particular theme.

The Q2 quadrant stands out for its themes, encompassing “gut microbiota,” “microbiome,” and “microbiota.” These themes have closer internal connections but relatively limited contributions in CRC immunotherapy research. Additionally, the emerging themes of “prognosis,” “tumor immune microenvironment,” and “immune infiltration” in the Q3 quadrant demonstrate limited relevance to CRC immunotherapy.

However, the themes of “microsatellite instability,” “PD-L1,” and “PD-1” in the Q4 quadrant have been extensively explored, suggesting a greater level of advancement in this area (Figure 7(c)). Further development is required in various areas including “tumor immune microenvironment,” “immune infiltration,” “prognosis,” “gut microbiota,” and other related themes, as indicated by the theme analysis. The exploration of these themes has reached important achievements and possesses considerable prospects for future studies in immunotherapy for CRC.

Similarly, we employed literature scintigraphy to visualize the key themes in CRC immunotherapy over the past two decades. Depicted in Figure 7(d), before 2009, research hotspots exhibited relative homogeneity, concentrating on cytotoxic T lymphocytes, interleukin-2, and gene therapy. Recently emerged keywords within the last two years include immune infiltration, drug resistance, and tumor microenvironment, suggesting their current status as research hotspots. The top five topics, based on overall frequency, were immunotherapy, colorectal cancer, colon cancer, tumor microenvironment, and prognosis.

Discussion

For this research, we utilized bibliometric methods and data visualization to thoroughly analyze 5251 papers on immunotherapy for CRC between 2002 and 2022.Our analysis integrates quantitative, qualitative, and synthesized approaches to delineate the evolution of the field and its future trajectory. The detailed results of our research will be discussed in the following sections, offering insights from various perspectives.

General information

The results demonstrate a consistent increase in the annual quantity of publications concerning CRC immunotherapy, signaling significant attention to this subject. Three pivotal turning points occurred in 2016, 2019, and 2021, possibly linked to major events in the field of CRC immunotherapy. In 2015, D.T. Le et al. validated that the status of mismatch-repair can predict clinical benefits of immune checkpoint blockade using pembrolizumab, sparking increased research interest.⁶ The Nobel Prize in 2018 recognized cancer immunotherapy with checkpoint inhibitors. And a significant achievement was reached on June 29, 2020, when the FDA provided approval for pembrolizumab to be used in the treatment of individuals with unresectable or metastatic MSI-H CRC.¹⁶ Consequently, CRC immunotherapy has emerged as a prominent research focus in recent years.

China leads globally with 1,653 publications in this area, followed by the USA and Italy with 1,536 and 375 publications, respectively. The distribution of organizations aligns with the countries, with China and the USA each contributing to half of the top 10 organizations. Sun Yat-sen University, Shanghai Jiao Tong University, and the National Cancer Institute (NCI) stand out with the most publication counts.

In the realm of authorship, each of the top 10 active authors has contributed a minimum of 10 articles, with Professor Romain Cohen leading the ranking with 15 papers. Furthermore, the works of the top 10 co-cited authors garnered at least 354 co-citations, signifying their substantial contributions to CRC immunotherapy. Le Dt (1113 co-citations) ranked first, followed by Galon J (655 co-citations) and Siegel RL (615 co-citations). Le Dt is renowned for the groundbreaking discovery that cancers with MMR deficiency display a heightened response to immune checkpoint inhibition using anti-PD-1 antibodies.^6,17 Frontiers in Immunology holds the highest number of publications in this area, whereas CLINICAL CANCER RESEARCH possesses the journal with the greatest H-index.

Knowledge base

A co-citation relationship is established when a subsequent paper cites two or more papers simultaneously.¹³ The significance of a paper increases with the frequency of its citations in a particular field. Researchers can comprehend major research findings and key concerns by analyzing the top 10 references that are frequently co-cited. Table 5 illustrates that most of these references are clinical trials published in top-ranked journals.

The PD-1 pathway functions as a system of negative feedback, suppressing Th1 cytotoxic immune responses, and it is upregulated in numerous tumors and the microenvironment surrounding them.^18–20 Significant clinical responses have been observed in patients with different types of cancer (such as melanoma and non-small-cell lung cancer) when antibodies targeting PD-1 or its ligands were used.^21,22 Nevertheless, the immune response elicited in colorectal cancer is frequently suboptimal compared to the more pronounced therapeutic effects of PD-1 inhibition in individuals with melanoma and lung tumors. This phenomenon has garnered significant attention from researchers. In 2015, Nicolas J. Llosa et al. demonstrated the immune microenvironment of DNA repair-deficient MSI CRC exhibited a robust Th1 and CTL component, in contrast to DNA repair-sufficient MSS tumors. In line with prior studies, this could be associated with the higher amount of “neoantigens” in tumors with DNA repair-deficient due to high mutational load.²³ Furthermore, it was discovered that MSI tumors exhibited significant upregulation of numerous immune inhibitory ligands, receptors, and metabolic enzymes, which elucidated the reason of tumor cells to survive despite the abundance of infiltrating activated lymphocytes.²⁴ In the same year, Dung T. Le et al. carried out a phase 2 trial (NCT01876511) to assess the effectiveness of pembrolizumab (an anti-PD-1 antibody) in individuals with advanced metastatic cancer, with or without mismatch-repair deficiency. Clinical trials have shown that dMMR CRC patients treated with pembrolizumab exhibit better response rates and survival times compared to pMMR CRC patients.⁶ Following that, this research team proceeded to examine the effectiveness of pembrolizumab in patients who had advanced cancers with mismatch repair deficiency. And this investigation encompassed 12 distinct tumor types (NCT01876511). The findings indicate that immune checkpoint blockade is effective against MMR-deficient tumors, regardless of the cancer tissue’s source.¹⁷ At the same time, Michael J. Overman et al. conducted an open-label, multicenter, non-randomized phase 2 trial (NCT02060188) in 2017 to assess the efficacy of nivolumab, a PD-1 immune checkpoint inhibitor, in individuals diagnosed with dMMR/MSI-H CRC. The results suggest that nivolumab can be a therapeutic option for dMMR/MSI-H mCRC patients to achieve better clinical responses, stable disease control, and prolonged patient survival.²⁵ In 2017, pembrolizumab and nivolumab received clinical approval from FDA as second-line therapies for individuals diagnosed with dMMR-MSI-H mCRC. One year later, Michael J. Overman continued to demonstrate the effectiveness and safety of the combination of nivolumab and ipilimumab for treating dMMR/MSI-H mCRC, based on the original trial (CheckMate-142). Excitingly, the results demonstrated improved efficacy of the combination immunotherapy over single anti-PD-1 therapy and a favorable benefit-risk profile.⁷ Thierry André et al. conducted an open-label, phase 3 trial (NCT02563002) to examine the effectiveness of pembrolizumab, as the first-line treatment for advanced or metastatic CRC with dMMR/MSI-H, in comparison to chemotherapy. Compared to chemotherapy, Pembrolizumab as the first-line treatment for mCRC with MSI-H – dMMR demonstrates extended progression-free survival, a more significant clinical benefit, a continuous clinical response, and reduced treatment-related adverse events.²⁶

In conclusion, these highly cited articles elucidate critical developmental nodes in CRC immunotherapy, encompassing distinctions of different subtypes of CRC in tumor microenvironments, exploration of immunotherapy in advanced tumors, and combination therapy. Analyzing these articles provides valuable insights to guide clinical care and comprehend the knowledge structure of CRC immunotherapy.

Emerging topics

Based on an analysis of highly cited literature and keywords in immunotherapy on colorectal cancer research, immune infiltration and the tumor microenvironment (TME) have emerged as focal points for researchers. Current studies highlight various crucial elements impacting immunotherapy, such as the tumor immune microenvironment, the immunogenicity of tumor, malfunction of MHCs, irreversible failure of T cells, and mutations in tumor genes.²⁷ Among these factors, the tumor microenvironment plays a pivotal role in tumor tissue formation, survival, and metastasis. The TME consists of diverse components, including tumor cells, fibroblasts, endothelial cells, pericytes, immune cells (both innate and adaptive), and non-cellular elements like extracellular matrix and soluble signals.^28,29 Due to its high heterogeneity and dynamic changes affecting immune cell infiltration in tumor tissues, it exerts an influence on PD-1/PD-L1 inhibitor effects.^27,30 Among these factors, the status of immune cell infiltration in tumor tissue is a crucial determinant for predicting a patient’s sensitivity to treatment with ICIs.³¹ Important roles are played by various factors including the extent of infiltration of CD8+ T lymphocytes in tumor tissues, the expression of PD-L1 in tumor cells, the quantity of CD4+ T lymphocytes, and the proportion of other immune cells in the microenvironment.^32,33 Moreover, various inhibitory components within the TME create an immunosuppressive microenvironment, such as cancer-associated fibroblasts (CAFs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and associated cytokines. This ultimately leads to the development of therapeutic resistance to ICIs.²⁷

Therefore, current research emphasizes focusing on the tumor microenvironment, with efforts directed toward remodeling the tumor immune microenvironment, enhancing CD8+ T-lymphocyte infiltration, and reversing the condition of immunosuppressive microenvironment to re-sensitize tumor cells to ICIs.

Due to the innate resistance of most mCRC to immunotherapy, the efficacy of single ICI treatment is limited. A promising avenue of research to enhance therapeutic sensitivity in mCRC involves combination therapy.³⁴ Combining ICIs with traditional radiotherapy, chemotherapy, and targeted therapy can alter the tumor microenvironment, enhancing the therapeutic impact to a certain extent. Research has shown that a small amount of decitabine enhances the activation of immune-related genes, such as major histocompatibility complex genes and cytokine-related genes. Additionally, it boosts the quantity of lymphocytes present at the tumor location in mice with CT26 colorectal cancer-bearing. In the CT26 mouse model, the combination therapy of PD-1 blockade and decitabine showed greater suppression of tumor growth and extended survival when compared to groups treated with decitabine or PD-1 blockade individually.³⁵ Radiotherapy has been a key focus of research for combination therapy due to its ability to effectively eliminate local tumor cells, increase tumor immunogenicity, stimulate local inflammatory responses, and enhance the infiltration of immune cells. In a recent study, the therapeutic effects of a combination involving ATR inhibitors (ATRi), radiotherapy, and anti-PD-L1 treatment were examined in CRC mice with different microsatellite statuses. In mouse models of CRC with different microsatellite statuses, the combination of ATRi berzosertib and radiotherapy enhanced STING signaling, leading to the activation of the innate immune response and the expression of type I interferon-related genes. This revitalized the cold tumor microenvironment, ultimately augmenting infiltration of CD8+T cells and improving efficacy of anti-PD-L1 therapy.³⁶ Furthermore, a recent study demonstrated a synergistic effect of regorafenib, a multikinase inhibitor, with anti-PD-1 therapy in murine models of microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer. Regorafenib greatly decreased the infiltration of immunosuppressive Treg cells and macrophages into the tumor microenvironment, whereas anti-PD-1 treatment significantly boosted IFN-γ levels within the tumor. This combination treatment approach synergistically and persistently mediated M1 macrophage polarization and Treg cell reduction, ultimately leading to tumor suppression.³⁷ Moreover, photothermal therapy (PTT), a novel cancer treatment, has demonstrated synergistic anti-tumor effects in combination with immunotherapy. Researchers have devised nanocomposites (GNC-Gal@CMaP) of hollow gold nanocage, integrating low-temperature PTT, PD-L1 antibody, and a TGF-β inhibitor. These nanocomposites selectively target colon cancer cells, accumulating in the tumor microenvironment, facilitating low-temperature PTT and inducing immunogenic cell death. Consequently, this activation triggers antigen-presenting cells, which in turn initiates the activation of effector T cells. This ultimately improves the effectiveness of the anti-PD-L1 antibody against tumors.³⁸

The gut microbiota, a prominent research topic in recent years, has been confirmed by studies to play a role in CRC development. Furthermore, studies have demonstrated that the gut microbiota and their metabolites can influence lymphocyte infiltration, immune cell ratios, and the state of the tumor’s immunosuppressive microenvironment, thereby affecting host responsiveness to ICIs therapy. Patients with immunotherapy-naïve mCRC showed an increased presence of Fusobacterium nucleatum and elevated succinic acid levels. This led to the development of immunotherapy resistance by blocking the cGAS-interferon-β pathway and limiting the transport of CD8+ T cells in the tumor microenvironment. The utilization of the antibiotic metronidazole proved effective in decreasing the presence of intestinal F. nucleatum and lowering serum succinic acid levels, ultimately restoring susceptibility to immunotherapy.³⁹ Another study suggests that F. nucleatum colonization in colorectal cancer leads to an immunosuppressive tumor microenvironment and reduces susceptibility to ICI therapy.

By combining the cytoplasmic membrane of F. nucleatum with liposomes loaded with Colistin, the scientists designed a nanomedicine that mimics F. nucleatum. And this nanomedicine selectively eliminates F. nucleatum while leaving other gut microbes unharmed, ultimately restoring ICIs treatment effectiveness in tumors colonized by F. nucleatum.⁴⁰ Simultaneously, probiotics also increase tumor sensitivity to ICI treatment. To manipulate the gut microbiome, the scientists employed Probio-M9, a strain of Lacticaseibacillus rhamnosus. Interestingly, Probio-M9 promotes the growth of advantageous microbes (e.g., Bifidobacterium animalis and Lactobacillus). Additionally, it boosts the production of beneficial intestinal metabolites such as butyric acids, and elevates the levels of beneficial metabolites in the blood including alpha-ketoglutaric acid, N-acetyl-l-glutamic acid, and pyridoxine. Probio-M9 ultimately inhibited the activity of Tregs, leading to the infiltration and stimulation of cytotoxic T lymphocytes (CTLs) within the TME.⁴¹

As the components of the tumor microenvironment (both cellular and non-cellular) are in dynamic equilibrium, the types and levels of metabolites within it are constantly changing. Due to metabolic alterations in the tumor and its proximity to the microbiota, metabolic wastes increase in the tumor microenvironment. It is not known whether these metabolite wastes will impact tumorigenesis, progression, and treatment. One study showed that high ammonia levels in the microenvironment induce metabolic reprogramming of T cells, leading to increased exhaustion and decreased proliferation.

Patients with CRC display increased levels of serum ammonia, and the gene signature associated with ammonia shows a connection with altered T cell response, unfavorable patient results, and an absence of response to immune checkpoint inhibition. Enhanced elimination of ammonia reinvigorates T cells, diminishes tumor growth, prolongs survival, and boosts the effectiveness of anti-PD-L1 antibody.⁴² Another investigation indicated that Treg activation is enhanced by hydrogen sulfide (H2S) through the persulfidation of ENO1 at cysteine 119.Simultaneously, H2S hinders the movement of CD8+ T cells by enhancing the AAK-1 expression through ELK4 persulfidation at cysteine 25. Reducing H2S levels significantly decreases the population of differentiated CD4+CD25+Foxp3+ Tregs and enhances the ratio of CD8+ T cells/Tregs. This ultimately reverses the status of immune microenvironment and improves the effectiveness of treatment with anti-PD-L1 and anti-CTLA4 antibody.⁴³

Limitations

Tools for visualization and analysis, like CiteSpace and VOSviewer, provide a comprehensive view of the evolution and trajectory of colorectal cancer immunotherapy. However, certain limitations exist within this study. The literature considered is not exhaustive, as only data from WoSCC was utilized, excluding data from other pertinent search engines. Additionally, our selected literature comprises only English publications, introducing language bias. Consequently, the analyzed literature may not fully represent all studies on colorectal cancer immunotherapy. Finally, bibliometrics studies on a similar topic have been published prior to our work.⁴⁴ However, the two articles exhibit differences in terms of time span, search strategy, results, and discussion content.

Conclusion

Comprehensive analysis shows immunotherapy already plays integral role in colorectal cancer treatment. The quantity of publications concerning immunotherapy for CRC has consistently increased year by year. The China, US, and Italy are among the leading countries that have made significant contributions to this area of research.

Among the institutions with publications in this field, the Sun Yat-sen University has the highest number of publications. Romain Cohen leads in the number of publications, while Le Dt stands out as the most influential author. The journal of Frontiers in Immunology possesses the highest total publications in this field. The journal with the greatest impact factor is CA-A Cancer Journal for Clinicians. The immune microenvironment and immune infiltration are emerging as key hotspots and future research directions in this domain.

CRediT authorship contribution statement

Si-fang Zhang contributed to the conceptualization and design of the study.

Qin-ling Ou and Yong-long Chang contributed to the conceptualization of the study, implementation of the research, and statistical analysis of the data. Jin-hui Liu collected and organized the data. Hai-xia Yan designed and produced the figures and tables. Lin-zi Chen and Duan-yang Guo completed the manuscript writing. All authors participated in the manuscript revision and read and approved the final manuscript for submission.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Additional information

Funding

This work was supported by the Research projects of Natural Science Foundation of Changsha (No. 2022467), Hunan Provincial Clinical Medical Research Center Project (No. 2023SK4048) and Hunan Shennong talent funding project.