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Clin Exp Med
Clin Exp Med
Clinical and Experimental Medicine
1591-8890
1591-9528
Springer International Publishing Cham

39230623
1480
10.1007/s10238-024-01480-3
Research
Investigation of pre and postoperative Th1/Th2 cytokine balance and novel cytokines in colorectal cancer patients
http://orcid.org/0000-0003-0189-5312
Gülçek Emre emregulcek89@gmail.com

1
http://orcid.org/0000-0002-2418-2393
Aydoğdu Yunushan Furkan 2
http://orcid.org/0000-0002-5399-7196
Emreol Umut İhsan 3
http://orcid.org/0000-0002-8066-5816
Bağrıaçık Emin Ümit 4
http://orcid.org/0000-0002-1877-355X
Akyürek Nusret 5
1 Department of General Surgery, Polatlı Duatepe State Hospital, Polatlı, Ankara Turkey
2 Department of General Surgery, Gölbaşı Şehit Ahmet Özsoy State Hospital, Gölbaş, Ankara Turkey
3 grid.414850.c 0000 0004 0642 8921 Department of General Surgery, Yenimahalle Training and Research Hospital, Yenimahalle, Ankara Turkey
4 https://ror.org/054xkpr46 grid.25769.3f 0000 0001 2169 7132 Department of Immunology, Faculty of Medicine, Gazi University, Yenimahalle, Ankara Turkey
5 https://ror.org/054xkpr46 grid.25769.3f 0000 0001 2169 7132 Department of General Surgery, Faculty of Medicine, Gazi University, Yenimahalle, Ankara Turkey
4 9 2024
4 9 2024
2024
24 1 21131 7 2024
26 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Colorectal cancer (CRC) is a major health problem worldwide and is usually detected in advanced stages, although it is highly treatable with early detection. The aim of this study was to examine the serum levels of various cytokines involved in the pathogenesis of CRC. The study included 29 patients and 30 healthy volunteers. Blood samples were collected twice from the patient group, before and after surgery, and these samples were evaluated for interleukin (IL) 4, 10, 23r, 37, 38, 40 and interferon (IFN) gamma levels. The results showed that IL-4 and IL-38 levels were significantly lower in the preoperative serum samples of the patient group compared to the control group (p < 0.001 and p = 0.01, respectively), while IL-4, IL-10, IL-38 and IL-40 levels increased significantly in the postoperative period (p = 0.004, p = 0.02, p = 0.03 and p = 0.004, respectively). These findings may contribute to the development of immunotherapy agents in the treatment of CRC. However, comprehensive studies on larger patient groups are needed to fully understand the role of cytokines in CRC pathogenesis.

Keywords

Cytokine
Colorectal cancer
Immunotherapy
Interleukin
Surgery
issue-copyright-statement© Springer Nature Switzerland AG 2024
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pmcIntroduction

Colorectal cancer (CRC) is a major health problem worldwide and is the third most commonly diagnosed cancer in men and the second most frequently diagnosed cancer in women according to GLOBOCAN data for 2020 [1]. Despite current treatment modalities (surgery, chemotherapy and radiotherapy), CRC-related mortality rates are still high, prompting scientists to develop new treatment modalities. Considering that inflammation plays an important role in colorectal cancer, it is of great importance to understand the molecular mechanisms, leading to intestinal inflammation in order to learn more about the pathogenesis of this disease. Recent studies have revealed that the most important components of these molecular mechanisms are cytokines. The identification of specific cytokines involved in the pathogenesis of colorectal cancer will pave the way for the development of new immunotherapy agents for this cancer type [2–4]. In recent years, immunotherapy, which has shown success in the treatment of different types of cancer, has become increasingly important in the treatment of CRC. For the effective use of immunotherapy in the treatment of CRC, the role of interleukins and other cytokines in the etiopathogenesis of CRC needs to be examined in detail. In CRC and other malignancies, the cellular immune response is thought to be initiated and maintained by IL-2 and IFN-gamma released from CD4 + T-helper 1 cells [5]. T-helper cells provide regulatory signals to CD8 + cytotoxic T lymphocytes (CTL), leading to apoptotic cell death in tumor cells. Therefore, tumor immunity is usually regulated by CTLs activated by T-helper 1 type cytokines. Although the T-helper 1/T-helper 2 balance may differ between cancer types, it is known that the T-helper 1 response is suppressed in most cancer types [6]. Interleukins have more than 40 members that act as signaling molecules in the immune system. They can interact with different cells to produce different effects in various cancers. Interleukins can cause tumor angiogenesis, growth, metastasis or tumor inhibition [5]. Inflammation plays an important role in the development of CRC and a disturbed balance of pro-inflammatory/anti-inflammatory effects contributes to this chronic inflammatory process. Therefore, studying the role of interleukins in CRC pathogenesis may lead to important changes in the treatment of the disease. In this study, we aimed to evaluate the association of serum levels of various interleukins (IL-4, IL-10, IL-23r, IL-37, IL-38, IL-40 and IFN-gamma), which have anti-inflammatory and pro-inflammatory effects, with CRC.

Materials and methods

The study was planned as a prospective case–control study. Between March 2022 and August 2022, 40 patients who were histopathologically diagnosed with colorectal cancer and operated on in the Department of General Surgery of Gazi University Faculty of Medicine Hospital were included in the study. A control group of 30 healthy volunteers was formed. The study was conducted with 29 patients and 30 volunteers after 11 patients were excluded from the study due to problems during serum transfer and patients failure to follow-up before adjuvant treatment. Due to the small sample size, results should be interpreted with caution. Pre/postoperative serum cytokine levels (IL-4, IL-10, IL-23r, IL-37, IL-38, IL-40 and IFN-Gamma) of colorectal cancer patients were analyzed; the same parameters were analyzed in the serum samples of the control group and comparisons were made. Patients over the age of 18 who were histopathologically diagnosed with colorectal cancer, who did not receive neoadjuvant and adjuvant chemoradiotherapy in the 1-month postoperative period and who did not develop complications in the perioperative period were included in the study. The control group was formed voluntarily from patients over 18 years of age with no history of chronic disease (inflammatory diseases that may affect cytokine serum levels, treatments that affect the immune response, other active infections or malignancies, cardiovascular events and severe organ deficiencies or injuries within the last 6 months) or malignancy who presented to the general surgery outpatient clinic of Gazi University Faculty of Medicine with non-specific symptoms. Patients who underwent surgery under emergency conditions, received neoadjuvant chemoradiotherapy and developed complications in the perioperative period were excluded from the study. A 10 cc peripheral venous blood sample was obtained from the patients who agreed to participate in the study in addition to the blood samples obtained for routine examinations in the preoperative period. Another 10 cc peripheral venous blood sample was obtained from the same patients at the 3rd–4th postoperative week. The blood samples obtained from the patient and control groups were kept in yellow gel tubes at room temperature for a maximum of 2 h and centrifuged in the laboratory of the Department of Immunology, Faculty of Medicine, Gazi University, and the serum samples obtained were stored at -86ºC. Blood samples were centrifuged at 3000 rpm for 10 min, and the sera obtained were stored at -86ºC and analyzed. Interleukin levels were analyzed by ELISA method using ready-made commercial kits (Bender MedSystems GmbH, Elabscience Biotechnology Inc., BT Lab, Abbexa LTD). The study protocol was approved by the Ethics Committee of Gazi University Faculty of Medicine (Date: July 4, 2022, Number: 666). All patients participating in the study were explained the study protocol, informed consent was obtained and an informed consent form for non-interventional clinical research was signed.

Statistical analysis

Statistical analyses were performed using SPSS 26.0 (IBM Inc, Chicago, IL, USA). Descriptive statistics of numerical and categorical data were analyzed, and numerical parameters were expressed as median (IQR). Categorical variables were expressed as frequency and percentage. Shapiro–Wilk test, histogram analysis and skewness/kurtosis data were used to evaluate the conformity of numerical variables to normal distribution. Since the numerical parameters were not normally distributed, non-parametric tests were used. Mann–Whitney U test was used for two independent group comparisons, and Kruskal–Wallis H test was used for independent multiple group comparisons. The dependent Wilcoxon test was used to compare parameters at different time points. Spearman’s correlation analysis test was applied for correlation between numerical parameters. Type-I error rate was taken as 5% in the whole study, and p < 0.05 was considered significant.

Results

The control group (CG) consisted of 20 men and 10 women. The patient group (PG) consisted of 19 men and 10 women. The median age of the PG was 64 years, while the median age of the CG was 59 years. There was no statistically significant difference between the two groups in terms of age and gender (Table 1). In PG, there were 10 patients in stage 1–2, 16 patients in stage 3 and three patients in stage 4. Preoperative cytokine levels of PG were analyzed and compared according to tumor stages. No significant statistical difference was found between the groups (Table 2). The statistical difference between the preoperative and postoperative cytokine values of PG was analyzed. Postoperative values of IL-4 (p = 0.004), IL-10 (p = 0.02), IL-38 (p = 0.03) and IL- 40 (p = 0.004) were found to be statistically significantly higher. In other parameters, no significant statistical difference was observed between the periods (Table 3). Statistical differences between the preoperative cytokine values of PG and CG were analyzed and compared. It was found that the IL-4 value was higher in CG compared to PG and this difference was statistically significant (p < 0.001). IL-38 was also found to be higher in CG compared to PG, and this difference was statistically significant (p = 0.01). No significant statistical difference was found in other parameters (Table 4). Our findings suggest that IL-4 and IL-38 may be a guide for immunotherapeutic agents to be developed for CRC.Table 1 Demographic data

Group	Gender (Male/Female)	Median age (Year)	P value	
Control Group (CG)	20/10	59	0.007	
Patient Group (PG)	19/10	64	0.007	

Table 2 Cytokine levels according to patient group stages

Cytokine levels	Stage 1–2 (n = 10)	Stage 3 (n = 16)	Stage 4 (n = 3)	P value	
IL-4 (pg/ml)	13.37 (11.37–73.508)	13.54 (11.67–19.97)	13.54 (11.67–19.97)	0.76	
IL-10 (pg/ml)	27.38 (16.91–93.109)	26.25 (17.94–33.524)	31.97 (20.18–34.944)	0.79	
IL-23r (ng/ml)	0.295 (0.241–0.665)	0.273 (0.246–0.520)	0.283 (0.232–0.351)	0.72	
IL-37 (ng/ml)	77.50 (73.45–105.20)	89.05 (72.56–90.26)	82.52 (76.14–87.16)	0.89	
IL-38 (ng/L)	40.11 (15.23–75.35)	45.33 (5.60–163.48)	44.43 (26.96–70.04)	0.34	
IL-40 (ng/ml)	18.66 (11.51–45.66)	15.38 (10.64–19.479)	17.88 (12.89–56.93)	0.90	
IFN-γ (pg/ml)	4.75 (2.94–30.28)	4.39 (2.10–10.10)	3.44 (2.55–14.68)	0.80	
IL: interleukin, IFN: interferon, pg: picograms, ml: millileters, ng: nanograms, L: liters,

Table 3 Preoperative and postoperative cytokine levels

Cytokine Levels	Preoperative	Postoperative	P value	
IL-4 (pg/ml)	13.54 (11.37–73.508)	14.09 (12.41–42.603)	0.004	
IL-10 (pg/ml)	26.28 (16.91–93.109)	51.32 (20.74–71.916)	0.02	
IL-23r (ng/ml)	0.309 (0.232–0.665)	0.313 (0.259–3.329)	0.08	
IL-37 (ng/ml)	82.52 (72.56–105.20)	119.30 (72.56–101.600)	0.09	
IL-38 (ng/L)	51.14 (5.60–163.48)	54.20 (25.16–231.75)	0.03	
IL-40 (ng/ml)	15.98 (10.64–19.479)	24.78 (11.33–182.85)	0.004	
IFN-γ (pg/ml)	4.25 (2.10–29.28)	4.89 (2.77–20.05)	0.06	
IL interleukin, IFN interferon, pg picograms, ml millileters, ng nanograms, L liters

Table 4 Patient and control group cytokine levels

Parameter	Patient group (PG)
Preoperative	Control group (CG)	P value	
IL-4 (pg/ml)	13.54 (11.37–73.508)	15.04 (13.14–17.92)	 < 0.001	
IL-10 (pg/ml)	26.28 (16.91–93.109)	25.27 (14.77–76.40)	0.86	
IL-23r (ng/ml)	0.283 (0.232–0.665)	0.292 (0.254–0.699)	0.20	
IL-37 (ng/ml)	82.52 (72.56–105.20)	99.51 (73.45–112.400)	0.49	
IL-38 (ng/L)	42.55 (0.60–163.0)	72.74 (0.30–239.96)	0.01	
IL-40 (ng/ml)	15.98 (10.64–19.479)	14.78 (10.47–61.71)	0.39	
IFN-γ (pg/ml)	4.25 (2.10–29.28)	4.59 (2.38–24.87)	0.15	
IL interleukin, IFN interferon, pg picograms, ml millileters, ng nanograms, L liters

Discussion

Despite advancing technology and medical advances, there is still a need for more effective methods in the treatment of CRC. The age of onset of CRC, which causes high morbidity and mortality especially in the elderly, is decreasing over time. CRC, which is a serious health problem in both men and women, has a higher prevalence in men [1]. In recent years, many studies have focused on cytokines, which are closely related to the immune system, cancer pathogenesis and inflammatory diseases [7–9]. The study by Lan T. et al. predicts that immunotherapy will be one of the most powerful weapons in the fight against cancer in the 21st century [10]. In CRC, infiltration of IFN-gamma, T-helper 1 and cytotoxic T cells is associated with improved patient survival [11]. The important role of IFN-γ in tumor immunosurveillance has been documented in preclinical models [12]. IFN-γ is secreted by immune cells and can exert long-distance effects by inducing a sustained response in tumor cells [13]. The study by Zhang Y et al. shows that increasing IFN-γ release inhibits the progression of colon cancer [14]. Consistent with the literature, this study showed that IFN-γ values were higher in the postoperative serum samples of the control group and the patient group compared to the preoperative serum values of the patient group, but there was no statistically significant difference. When the patient group was evaluated according to cancer stages, it was observed that IFN-γ serum values decreased as the stage progressed, but there was no statistically significant difference. The effect of interleukin (IL)-4 on the development of CRC has not yet been fully clarified [15]. In the study by T. Kantola et al., IL-4 serum levels were found to be higher in the CRC group compared to the control group, but no significant statistical difference was found. In the same study, IL-4 serum values were compared according to cancer stages, but no significant statistical difference was observed [16]. In the literature, there are studies indicating that the effect of IL-4 on CRC development may be in both positive and negative directions [17, 18]. In this study, IL-4 serum levels were significantly lower in the preoperative period in the patient group compared to the control group. Although there was an increase in the values seen in the postoperative period, there was no significant difference compared to the preoperative period. When the preoperative IL-4 serum values of the patient group were compared according to cancer stages, no significant difference was observed. In Abtahi S. et al. study, the effect of IL-10 on the pathogenesis of CRC was examined and it was reported that serum IL-10 levels were higher in the healthy volunteer group than in the group of CRC patients [19]. In the study of Ma Y. et al., IL-10 serum levels were found to be significantly higher in CRC patients compared to the control group [20]. In this study, although IL-10 serum values were higher in the patient group, no significant difference was found. In another study, high IL-10 serum levels were associated with poor prognosis in CRC patients [21]. In addition, IL-10 serum levels were not associated with the stage of the disease. The prognostic significance of IL-23 in CRC is unclear. Hu et al. reported that high IL-23 expression was associated with poor prognosis and could be used as a prognostic biomarker for CRC [22]. In Lan F. et al. study, IL-23r levels were found to be significantly higher in tissues containing CRC cells compared to healthy tissues [23]. However, no statistically significant difference was found between IL-23r levels in this study. In addition, there was no significant difference in the comparison of IL-23r serum values according to the stages and pre/postoperative IL-23r serum values in the patient group. When the studies on IL-37 in the literature are examined, it is suggested that IL-37 levels are decreased in tissues with CRC cells compared to healthy tissues and IL-37 plays a protective role [24, 25]. In this study, IL-37 levels did not show a significant difference between the patient and control groups. In addition, no significant difference was found in the comparison of IL-37 serum values according to the stages in the patient group and in the comparison of pre/postoperative IL-37 serum values. Dysregulation of IL-38, an anti-inflammatory cytokine, is observed in many autoimmune diseases. Decreased colonic IL-38 is associated with CRC invasion and metastasis, and IL-38 is thought to have a protective role in the tumor microenvironment [26, 27]. Chen F. et al. found that IL-38 levels were significantly lower in cancerous tissues of CRC patients compared to intact tissues [28]. In this study, serum IL-38 levels were found to be significantly lower in the preoperative period of the patient group compared to the control group. In addition, a significant difference was observed in the postoperative period in the comparison of pre/postoperative IL-38 serum values. However, no significant difference was found in the comparison according to CRC disease stage. There are very few studies in the literature on the relationship between CRC pathogenesis and IL-40. IL-40 is a novel cytokine involved in humoral immune responses and B cell homeostasis [29, 30]. Decreased serum levels of IL-40 may alter the gut microbiota by decreasing immunoglobulin A levels [31]. In this study, there was no statistically significant difference between the preoperative serum IL-40 levels of the patient group and the serum IL-40 levels of the control group. However, a significant difference was found in the postoperative period in the comparison of pre/postoperative IL-40 serum values. Our study was meticulously designed and implemented to compare the changes in serum cytokine levels during the preoperative and postoperative periods. We were able to improve the accuracy and reliability of the data by excluding patients whose disease could be affected by various factors. This approach allowed us to clearly demonstrate the changes in cytokine levels between the preoperative and postoperative period. One of the important advantages of our study is that the patient population was well-defined and homogeneous. This made it possible to accurately monitor and evaluate changes in cytokine levels. Furthermore, the methodological approaches and rigorous data analysis used in our study increase the reliability and validity of the results obtained. Despite being a single-center study, the consistency and validity of the data obtained strengthen the clinical relevance of our results. The advanced statistical methods and careful data analysis provided a solid scientific basis for our findings. Our study has made important contributions to the literature on the monitoring of changes in cytokine levels in the preoperative and postoperative periods. Considering the limited number of studies in this field, the usability of our findings in clinical practice and their reference quality for future research further reinforces the success of our study. Our results helped us to better understand the immunologic effects of surgical interventions and increased the knowledge in this field. In this study, we tried to better understand the immunologic dynamics of colorectal cancer by examining the changes in serum cytokine levels in the preoperative and postoperative periods. In the preoperative period, IL-4 and IL-38 levels of the patient group were significantly different from the control group. These different cytokine levels may influence CRC progression by modulating the tumor microenvironment. Future studies should investigate targeting these cytokines for therapeutic interventions in CRC. Our study constitutes an important step to better elucidate the role of cytokines in colorectal cancer pathogenesis. However, comprehensive studies on larger patient groups are needed in this field. Such studies may contribute to the development of new immunotherapy agents in cancer treatment and pave the way for more effective and targeted approaches in colorectal cancer treatment. Future research should investigate how the findings can be integrated into clinical practice and improve patient's quality of life.

Conclusion

Colorectal cancers stand out as one of the biggest challenges for healthcare systems worldwide. Although significant advances have been achieved in this cancer type thanks to innovations in surgical techniques and chemoradiotherapy, disease-free survival rates do not reach the desired level due to the lack of obvious symptoms and limited chance of early diagnosis. In this context, understanding the immune mechanisms involved in the pathogenesis of colorectal cancers offers great contributions to both diagnosis and treatment processes. The development of immunotherapy in recent years has led to promising results not only in early stage disease but also in advanced stages. Future research should focus on larger, multicenter studies with longer follow-up to confirm these findings and investigate the therapeutic potential of cytokine modulation in CRC. Our study provides new insights into the cytokine profile of CRC patients, highlighting potential biomarkers for disease progression and response to therapy. Such research will contribute significantly to the development of innovative immunotherapeutic agents and the improvement of current treatment strategies in cancer treatment.

Acknowledgements

There are no acknowledgments.

Authors contributions

YF.A., E.G. and Uİ.E. wrote the main manuscript text. EÜ.B. and N.A.. prepared tables. All authors reviewed the manuscript.

Funding

The authors declared that this study has received no financial support.

Data availability

The database of this study is open to sharing. It can be obtained from the authors upon request.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Consent for publication

Consent for publication was obtained from all participants.

Ethical approval

Approval for this study was obtained from the Gazi University Faculty of Medicine Institutional Review Board Ethics Committee, and signed informed consent forms were obtained from all patients.

Human and animal rights

All procedures performed in this study were by the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its subsequent amendments or similar ethical standards. No animal or human studies were performed by the authors for this article.

Scientific responsibility

The authors declare that they are responsible for the scientific content of the article, including study design, data collection, analysis and interpretation, writing, part or all of the outline, preparation and scientific review of the content and approval of the final version of the article.

Publisher's Note

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