Esophageal cancer is the seventh most common malignant cancer all over the world and the sixth leading cause of cancer mortality (1). In 2018, 508,585 esophageal cancer-related deaths occurred globally (2). Approximately 90% of the pathological types of esophageal cancer are esophageal squamous cell carcinoma (ESCC) (3, 4). For the treatment of ESCC, traditional curative esophagectomy was a major selection. However, in patients with locally advanced esophageal cancer (T_3–4aN_0–1M₀), only radical resection is accompanied by a high recurrence rate and mortality rate of 3- to 5-year overall survival (OS) (5, 6). Therefore, combined modality therapy is necessary. Some studies indicated that when compared with preoperative chemotherapy or surgery alone in patients with locoregional esophageal cancer, neoadjuvant chemoradiotherapy was connected with improved OS and disease-free survival (DFS) (7–11). Several markers (such as Rad51, osteopontin, plasma fibrinogen, and soluble interleukin-6 receptor) have also been reported to be associated with the prognosis of ESCC patients who received preoperative chemoradiotherapy (12–16). However, the treatment effect and prognostic indicator before neoadjuvant chemoradiotherapy still need further research.

This is a broad consensus that TNM staging is pivotal and irreplaceable for the diagnosis and treatment of tumors including esophageal carcinoma. Clinical studies indicated that the TNM stage is an independent prognostic factor for OS (17, 18). However, the classification of the cTNM stage mainly depends on computed tomography (CT) and endoscopic ultrasonography (EUS). Studies reported that the sensitivity of EUS (usually less than 50% sensitivity) for detecting metastatic nodes was low. The specificity to discriminate the N0 from a node-positive disease of CT was just 38.7%, and CT was unreliable for local staging (19–21). Based on these findings, only depending on a single cTNM stage may lead to deviations in the accuracy of prediction when establishing a prognostic model for ESCC patients with neoadjuvant chemoradiotherapy (nCRT) plus surgery. Therefore, it is necessary to construct a multivariate prognostic model.

It is increasingly recognized that cancer-related inflammation (CRI) is related to tumor progression. Inflammation in tumor microenvironments can promote cell proliferation and inhibit the adaptive immune response (22). Systemic inflammation score (SIS) has played an independent role in the prognosis of ESCC patients (23). In cancer-related immunology, immune cells exerted anti-tumor capacity through different mechanisms such as binding ligands on the surface of tumor cells through self-surface receptors; meanwhile, pro-inflammatory and immunomodulatory cytokines such as IL-12, TNF-α, IFN-γ, and IL-6 were released during the process. These cytokines would cause changes in other inflammatory substances such as C-reactive protein (CRP). In the cancer immunoediting process, antibodies are involved in the event of antibody-dependent cell-mediated cytotoxicity. Moreover, the level of different antibodies was variable in tumor location or blood (22, 24). The connection between cancer-related inflammation and immunology is tight. The antibody, inflammatory factor, and cytokine generated the re-sculpting of the tumor immune and inflammatory microenvironment (25). However, the relationship between serum immune and inflammation indicators and prognosis with ESCC patients who received nCRT plus surgery is indistinct. The target of the study was to construct a nomogram constructed with immune and inflammatory indicators. Through this nomogram, we can macroscopically recognize the benefit that ESCC patients could obtain after nCRT plus surgery.

Esophageal cancer as the sixth leading cause of cancer death causes huge economic pressure, especially for developing countries, and many of the tumors will have progressed to advanced stages during the diagnosis. Moreover, the benefit rate of surgery alone in advanced patients was low (1, 3, 4). Neoadjuvant chemoradiation is recommended for advanced esophageal cancer patients. Chemotherapy medicines such as carboplatin, paclitaxel, cisplatin, and fluorouracil were frequently selected in combination therapy with radiation, and the pathological complete response and overall survival rate were improved as compared with surgery alone (28, 29). Nevertheless, the benefit rate of nCRT was closely related to the individual. Therefore, it was necessary to establish a prognostic model for ESCC patients who received nCRT. As research reported, the DFS was shorter for the patients with preoperative hyperfibrinogenemia (fibrinogen > 350 mg/dl), and the plasma fibrinogen level was a biomarker for predicting postoperative recurrence (14). Although some prognostic indicators were confirmed as independent risk factors for OS or DFS, most of them were single indicators. This meant the predicted bias may exist for prognosis. Further, the significance of the model based on combined indicators deserved to evaluate. Here, we established the nomogram model according to the preoperative cTNM stage, serum CRP, and IgA for predicting the prognosis of ESCC patients receiving nCRT plus surgery and verified the nomogram in the validation cohort. Our nomogram showed improved prediction accuracy for prognosis, compared with the cTNM stage.

The connection between cancer-related inflammation and protective tumor immunity is dynamic. Consequently, evaluating the immune and inflammation status of tumor patients was of positive significance for prognosis. CRP, which existed in the form of pentamer in plasma, was synthesized mainly by hepatocytes (30–33). As an acute reaction protein, under normal circumstances, the content of CRP in human serum was low, but the CRP concentration even increased 1,000-fold in response to inflammation or tissue damage (34). Several studies reported that the high level of CRP as an independent prognostic factor was connected with OS in gastric, lung, ovarian, and esophageal cancers (35–40), and the high preoperative or postoperative CRP levels were related to worse survival prognosis in ESCC patients (35, 40–42). These results were consistent with the finding of serum CRP observed in our study. Survival analysis showed that a high CRP level (≥4.4 mg/L) before nCRT plus surgery was associated with worse OS. In our nomogram, CRP had a strong effect on predicting OS. IgA, which was produced by plasma cells, existed in the mucous membrane, tissues, and blood. Furthermore, IgA was the second most abundant immunoglobulin isotype in serum. IgA drove passive immunity-related functions. Recently, IgA-induced inflammation in diseases has been discussed (43, 44). Furthermore, as reported by Shalapour et al., IgA+ cells induced by an inflammatory environment dismantled anti-liver tumor immunity (45). IgA, which effectuated an important role in the diagnosis of chronic lymphocytic leukemia (CLL), was an independent prognostic factor for disease progression, survival, and infection in CLL (46). However, studies about the prognostic prediction ability of IgA on solid tumors were insufficient. In our work, we revealed that IgA was an independent risk factor for OS of ESCC patients who received nCRT plus surgery, and survival analysis revealed that high IgA level (≥3.0 g/L) was related to worse 1- or 3-year OS.

In our study, the prediction accuracy of the nomogram was satisfactory, as the C-index of the nomogram adopting internal verification through the Bootstrap algorithm was 0.820 (95% CI: 0.705–0.934) in the training cohort and 0.832 (95% CI: 0.760–0.903) in the validation cohort, which was higher than those of any other single indicators including the cTNM stage. DCA, IDI, NRI, and calibration curve consistently certified that the net benefit, model fit, and accuracy of nomogram were satisfactory in both cohorts. These consequences confirmed that the prognostic prediction of the nomogram established with the levels of immunity and inflammation-related indicators was reliable.

However, the shortcomings of our study still existed. Firstly, the sample size was relatively small in our study. This may cause a bias in the results. For example, the TNM stage was generally used to evaluate cancer patient survival in clinical practice. However, in our study, the cTNM stage was statistically related to patient survival, but not an independent prognostic factor in multivariate Cox analysis. This is mainly attributed to the small sample size and the majority of enrolled patients with advanced stage. In the future, expanding the samples is important to address this issue. Secondly, both the training cohort and the validation cohort were from the same hospital. Arrangement of the verification in external cohorts was required in the future. Thirdly, the retrospective nature of analyses was another limitation of this work. Thus, further research with prospective design is warranted to validate our constructed nomogram.

In our study, we established a nomogram based on serum IgA, CRP, and cTNM stage to predict the prognosis of ESCC patients receiving nCRT plus surgery. The predicted ability, accuracy, and applicability were satisfactory, which were verified in a validation cohort.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Hospital Ethics Committee in the Cancer Hospital of Shantou University Medical College. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

YL and X-FW designed the study, collected and analyzed the patient samples and clinical data, and wrote the manuscript. J-TH and X-HH collected patient samples and clinical data, analyzed and interpreted the clinical data, and revised the manuscript. L-FW, Y-WL, and T-YD collected patient samples and clinical data, analyzed the data, and revised the manuscript. BZ, L-YC, and C-TL collected patient samples and clinical data, analyzed the clinical data, and revised the manuscript. Y-HP, Y-WX, and F-CW conceptualized and designed the study, supervised the project, and revised the manuscript. All authors contributed to the article and approved the submitted version.

This work was funded by grants from Science and Technology Planning Project of Shantou City (No. 220506106490650), the Natural Science Foundation of China (No. 81972801), Guangdong Basic and Applied Basic Research Foundation (No. 2019A1515011873), and 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant (No. 2020LKSFG01B).

The authors thank the Department of Clinical Laboratory Medicine of the Cancer Hospital of Shantou University Medical College for their contributions to data collection and analysis.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.