Recently, systemic inflammation has been found to correlate with tumor progression. Leucocytes in the tumor microenvironment promote tumor growth, angiogenesis and metastasis Many peripheral inflammatory markers including PLR, NLR and LMR and their prediction of clinical outcomes in solid tumor entities have been uncovered [13, 14] In this study, we examined a large cohort of patients with advanced typeⅡ/Ⅲ AEG and investigated the prognostic significance of preoperative lymphocyte to monocyte ratio as a biomarker for predicting the outcomes after radical surgery.
As we all know, lymphocytes play an essential role in systemic inflammatory response to tumorous disease, including the inhibition of tumor cell proliferation and migration . lymphocytes are the important components of the adaptive and innate immune system and the cellular basis of immunosurveillance. A decreased lymphocyte count is assumed to reflect an insufficient immunologic reaction to the tumor, thus promoting tumor cell apoptosis and metastasis .Some studies have shown a prognostic impact of tumor-infltrating lymphocytes (TILs) in a series of cancers including gastric cancer[17, 18]. In the study of gastric adenocarcinoma, dense infltration of CD3 + and CD8 + TILs had been associated with an optimistic prognosis . In esophageal adenocarcinoma, the lower level of the FOXP3 + regulatory T cell (Treg) infltrate present in the residual tumor or scar correlated with the more pathological response . In resent study, Higher levels of TILs in the pathological specimen were associated with signifcant pathological response to neoadjuvant chemotherapy (NAC), increased levels of CD4 + and CD8 + TILs were associated with signifcant local tumour regression and lymph node downstaging.
The role of monocytes in tumor invasion, proliferation and metastasis is important. Monocytes can differentiate into tumor-associated macrophages(TAMs) in the tumor microenvironment. TAMs are recruited at the tumor site, where they accelerate tumor progression through the angiogenesis and anti-immune responses. More and more evidence show that tumor-associated macrophages(TAMs) suppress the immune system of the host and promote tumor angiogenesis, proliferation and migration . Macrophages are capable of producing osteonectin, which is essential in forming metastasis. This evidence suggests a tumorous potential of monocytes due to formation of different macrophage phenotypes that promote the malignant process. The high absolute monocytes count in the peripheral blood is reported to stand for the formation of TAMs and an elevated tumor burden in patients. Therefore, it is not surprising that peripheral blood monocytosis is an adverse prognostic factor for various tumors. The LMR might be a good reflection of responsiveness of the immune system of the host and a microenvironment marker of tumor burden. The prognostic values of LMR in patients with AEG remain uncertain.
In our study, we set 3.64 as the cut-off levels for the LMR by applying ROC curve analysis, different from some other studies, such as 4.0 in the study by Hirahara N, 2.86 in pancreatic adenocarcinoma by Li’s study, a decreased peripheral lymphocyte to monocyte ratio (LMR) has been identifed as a poorer prognostic indicator in various cancers[26, 27].From Table 2, we found that the median of Lymphocyte count was higher in ‘LMR༞3.64’(1.9) than in ‘LMR ≤ 3.64’(1.3). The median of monocyte count was nearly the same in two groups(0.3vs0.4). 5-year CSS with ‘LMR༞3.64’ was 51.8% higher than 43.2% with ‘LMR ≤ 3.64’ (P = 0.008; Fig. 2D). Sometimes TAMs not only enhance tumor growth and progression, but also modulate the efficacy of various forms of anticancer therapy, such as chemotherapy and radiotherapy. In some circumstances, they also facilitate tumor regrowth, revascularization, and spread after the treatment. In patients with esophageal cancer, infiltration with CD68 + and CD163 + TAMs, especially M2 macrophages, is associated with a poor prognosis for patients undergoing neoadjuvant chemotherapy. Not only the first-line chemotherapeuitc drug, but also epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had a poor response in patients with advanced non-small cell lung cancer. As we all know, how to predict whether patients of AEG can benefit from chemotherapy was still a problem which perplexed physicians for many years. Our results suggest that ‘high-risk’ patients based on LMR ≤ 3.64 do not benefit from 5-fluorouracil-based adjuvant chemotherapy. For high-risk patients of AEG, we should avoid to use of adjuvant 5- fluorouracil -based chemotherapy until disease progression. Moreover, the LMR provides an easy available and low price biomarker with outcome.
To the best of our knowledge this is the first study to assess the LMR in advanced type II/III AEG. The strength of this study is the large sample size and the long follow-up period. However, there are some possible limitations associated with this study. Firstly, because of the retrospective design of the study, we cannot fully exclude the selection bias in our cohort. Furthermore, potential confounding factors such as infection, coronary syndrome, and diabete mellitus, that might affect the lymphocyte and monocyte count were not taken into consideration. Finally, although we set 3.64 as the cut-off level by using ROC curve, different cut-off levels may also valuable. So large prospective and multi-centric clinical trails should be performed to confirm our findings in future.