This is the first study to examine the relationship between ICI therapy and the nutritional status in patients with esophageal cancer. In our study, ICI-treated esophageal cancer patients in the high CONUT group (CONUT > 1) had significantly worse OS and PFS compared to the low CONUT group (CONUT ≤ 1). We also found that the CONUT score was an independent predictor of ICI treatment effect and OS. We therefore believe that the CONUT score may serve as a potential early predictive marker in esophageal cancer patients who want to benefit from ICI therapy.
The CONUT scores included serum albumin and total cholesterol and total lymphocyte count in peripheral blood. Serum albumin mainly reflects the body's ability to synthesize protein, serum total cholesterol reflects the body's ability to metabolize lipids, and the total lymphocyte count in peripheral blood reflects the body's immune function . Subjective Global Assessment (SGA) and the Full Nutritional Assessment are relatively complex, while the CONUT score provides an easier and more objective assessment of a patient's nutritional status . Thus, a higher CONUT scores could reflect not only malnutrition, but also systemic inflammation and an impaired immune responses. In addition, the CONUT scores can be retrospectively studied in relation to clinical outcomes. Therefore, we retrospectively investigated the relationship between the CONUT scores and patient outcomes. We found that the proportion of patients with a lower CONUT score in the low NLR group tended to be significantly higher than the proportion of patients with a low CONUT score in the high NLR group (Table 3). One possible explanation is that both the COUNT score and the NLR are related to the total lymphocyte count in peripheral blood.
Previous studies have reported the influence of the CONUT score on preoperative prognosis [27, 28]. Studies have shown that the CONUT score is an independent prognostic factor for relapse-free survival (RFS) and OS in patients with resectable thoracic esophageal squamous cell carcinoma (ESCC) .Recently, it was reported  that the CONUT score could be used to predict the prognosis of non-small cell lung cancer patients receiving pembrolizumab. In this report, compared with the high CONUT score group (CONUT > 2), the low CONUT score group (CONUT ≤ 2) was associated with significantly longer PFS and OS. And they found that the CONUT score were independent prognostic factors of OS (P < 0.05). However, this retrospective study had a small number of patients and may be biased. Currently, there are no relevant reports on the CONUT score in predicting treatment outcome in patients with esophageal cancer treated with ICI. In the present study, we show for the first time that patients with esophageal cancer with the high CONUT score treated with ICI had significantly worse OS and PFS compared with patients with the low CONUT score.
ICI is a cancer therapy that targets co-inhibitory signaling on the surface of T cells, resulting in long-lasting antitumor responses by disabling the braking mechanism of the immune system . Phase II clinical trials ATTRACTION-1 study and KEYNOTE-180 study showed the efficacy and safety of ICI as third-line treatment of advanced esophageal cancer [5, 11]. In 2019, the phase III KEYNOTE-181  study showed that among patients with a PD-L1 combined positive score (CPS) ≥ 10, the mOS in the pembrolizumab group was 9.3 months, compared with 6.7 months in the chemotherapy group, and there was no significant difference in PFS between two groups. Subgroup analysis found that Asian patients benefited more from pembrolizumab treatment. The results of the ATTRACTION-3 study showed that , regardless of the level of PD-L1 expression in patients, the nivolumab group could improve the OS of patients by 2.5 months and reduce the risk of death by 23%. More and more studies have demonstrated the safety and efficacy of ICI in patients with advanced esophageal cancer. ONO4538 is a phase II clinical study  to investigate the efficacy of nivolumab in patients with advanced ESCC who are refractory or intolerant to fluoropyrimidine, platinum and taxane chemotherapy. The results showed an OS of 10.8 months and a PFS of 2.8 months, suggesting that nivolumab may be a potential treatment option for patients with advanced ESCC who are refractory or intolerant. At this stage, we still need to further explore the role and mechanism of ICI in patients with esophageal cancer, so that more advanced esophageal cancer patients can benefit from ICI.
As immunotherapy plays an increasingly important role in cancer treatment, the research on tumor biomarkers related to its therapeutic effect is also continuously applied. Biomarkers currently used to assess whether there is a good response to immunotherapy mainly include PD-L1 expression, tumor mutational burden (TMB), and microsatellite instability (MSI). The expression of MHC-II molecules , CD8 expression in tumor-infiltrating lymphocytes (TIL) and lack of DNA mismatch repair system  have also recently been shown to be biomarkers. Neoantigen  is another biomarker that has been used to predict the effect of anti-PD-1 therapy in esophageal cancer. However, the correlation between these biomarkers has not yet been investigated, so we plan to study the correlation of various biomarkers in ICI treatment in the future.
This study has certain limitations. First, because this study was a single-institution retrospective study, the number of patients treated with ICI was relatively small. In addition, many patients are lost because serum total cholesterol levels are not considered important in esophageal cancer chemotherapy treatment. Third, the current retrospective study cannot include factors that may influence inflammation and nutritional status. Therefore, we need prospective studies to overcome these problems.
In conclusion, the CONUT score can be used as a biomarker to predict the efficacy and prognosis of esophageal cancer patients receiving ICI therapy, and can be used to guide advanced esophageal cancer patients who want to benefit from ICI therapy.