We revealed the prognostic value of NLR, an indicator of systemic inflammation, in gastric cancer. The NLR-adjusted pTNM staging had a better predictive value for patient prognosis when compared with the traditional pTNM staging system. In addition, a higher NLR was associated with advanced-stage gastric cancer. Infiltration of CD3 + and CD8 + T cells was significantly different in patients with different levels of NLR. These findings indicate that systemic inflammation involves in the development and progression of gastric cancer. The peripheral blood NLR could be used to reflect the cancer-immune microenvironment and to predict the patient with a worse prognosis who might need aggressive postoperative adjuvant therapy.
In recent years, our understanding of the cancer-immune microenvironment has greatly improved. Lymphoid regulatory cells include regulatory T, B, and NK cells in the tumor site, have been reported to support cancer growth, migration, and metastasis . Cancer-associated myeloid cells are involved in cancer cell biology, including proliferation, invasion, distant metastasis, and the development of resistance to therapy . STAT3 played a role in several crosstalk levels between tumor cells and the immune microenvironment, and mediated tumor-induced immunosuppression . Helicobacter pylori (HP) infection-induced chronic inflammation is a significant factor for gastric cancer . The development of gastric cancer is attributed to genetic alterations caused by chronic inflammation, recruitment of immune cells, an imbalance between epithelial cell proliferation and apoptosis, and gastric colonization by enteric bacteria. Increased expression of pro-inflammatory cytokines and chemokines such as IL-17A, IL-22, and IL-1 family members IL-1β are involved in gastric cancer progression . Thus, systemic inflammation might play an essential role in the gastric cancer microenvironment. Besides these pieces of molecular biology evidence, our results provided more information about systemic inflammation and tumor microenvironment from the perspective of clinical prognosis through mediation analysis.
Lymphopenia is an impaired cell-mediated inflammatory response, whereas neutrophilia is an immune response that triggers tumorigenesis . NLR can be used to represent a balance between pro-tumor and antitumor immunity. The NLR also can reflect the cancer burden and tumor biological behavior. Kei Nakamura, et al showed that NLR was associated with undifferentiated histology, advanced clinical T stage and N stage . Kazuhiro Migita, et al concluded NLR might be associated with the extent of tumor spread at the time of recurrence . Consistent with previous studies, we found that a high level of NLR was associated with the late tumor stage. The TNM stage system is always be used to predict the prognosis of cancer and guide postoperative treatment. Nevertheless, prognosis differs greatly among patients with the same tumor stage, which indicates that other prognostic factors should be included to optimize the system. Previous studies have reported the prognostic value of NLR in gastric cancer with the cutoff value set as 3 mg/dL [11, 22, 23]. Similarly, in our study, patients were also divided into two groups based on the level of NLR. The NLR-adjusted pTNM staging system allowed more accuracy to predict the prognosis of gastric cancer. NLR is an independent prognostic predictor of gastric cancer. Taken together, we conclude that NLR can be proposed and used as a predictor to stratify patients with different prognosis.
Lymphocytes are associated with a favorable prognosis in multiple tumors. The NLR is associated with the density of CD4 + T cells in gastric cancer . It also negatively correlated with CD8 + T cells infiltrating in biliary tract cancer . High NLR is significantly associated with high neutrophil infiltration and low CD3 + T cells in glioblastoma . Here, we showed that the infiltration of CD3 + and CD8 + T cells was both significantly different in patients with different levels of NLR. The infiltration level of CD3 + T cells was the mediating factor between NLR and survival prognosis. Thus, the NLR might serve as a valuable indicator for evaluating the immunoreactivity in the gastric cancer microenvironment.
The NLR was thought to be correlated with the tolerability and response to anticancer therapy in multiple cancers [26–28]. NLR might be valuable for screening patients who will benefit from palliative chemotherapy. In our study, 88.2% of patients were with locally advanced/advanced gastric cancer. Many of them were treated with postoperative chemotherapy after D2 radical gastrectomy. Surprisingly, the effect of NLR on the patient prognosis prediction was affected by MMR status. MMR status is a mature biomarker for predicting the efficacy of immune checkpoint inhibitors. This might indicate that the NLR level is associated with the efficacy of immune therapy and that markers of systemic inflammation could be used to predict immune responses in cancer therapy.
There are some limitations in this study. Firstly, this is a retrospective study in which patient selection bias might exist. Secondly, the cutoff value of NLR is needed to be verified in a multicentric, independent cohort. Thirdly, we did not evaluate the postoperative dynamic changes in the NLR. Lastly, the assessment of some reported systemic inflammation indicators, such as CRP, was not included in this study. Larger prospective studies are needed to evaluate these issues. However, despite the limitations mentioned above, we evaluated the mediation effects of tumor microenvironment on the association between systemic inflammation and overall survival for the first time. In addition, we demonstrated that the NLR was able to improve the predictive accuracy of the TNM model and describe the relationship between NLR and immune checkpoints.