Clinical value of peripheral blood NLR in predicting the prognosis of MMBD patients treated with operation
Multiple myeloma is a malignant proliferative disease of plasma cells, whose occurrence and development are strongly dependent on the micro-environment. The interaction between MM cells and the micro-environment plays a crucial role in the pathogenesis of MM[10–12]. MM's micro-environment is mainly composed of inflammatory cells (including macrophages, dendritic cells, mast cells and myeloid-derived suppressor cells), which are the main source of MM infiltrating bone marrow cytokines and mediate immune suppression of MM[13–16]. Inflammation is one of the characteristics of malignant tumors, and tumor-related inflammation plays an important role in promoting tumorigenesis by inducing tumor cell growth, angiogenesis and genomic instability[17]. Neutrophil-lymphocyte ratio is a readily available indicator of systemic inflammatory reaction[18]. As a simple and inexpensive tool, NLR has been more and more reported to have predictive and prognostic value in solid tumors, such as gastric cancer, liver cancer and ovarian cancer. Elevated NLR indicates poor prognosis in patients, but its mechanism is not yet clear. And there are few studies on hematologic tumors[19–23]. NLR has been reported to be of great value in the prognosis of MM patients. Studies have shown that elevated NLR is associated with declined OS in MM patients receiving bortezomib induction therapy[24]. Studies have also shown that elevated NLR and declined platelet-lymphocyte ratio (PLR) are independent prognostic factors for progression-free survival of MM patients[25]. Therefore, elevated NLR and declined monocyte-lymphocyte ratio (MLR) and PLR predict adverse clinical outcomes in MM patients, and may serve as cost-effective and readily available prognostic biomarkers[26]. So far, there are no reports on the prognostic value of NLR in MM patients treated with operation. Results in the study showed that the NLR cut-off values of the preoperative peripheral blood NLR ≥ 3 group and the preoperative peripheral blood NLR ≥ 4 group were significantly correlated with the POS and postoperative cumulative survival rate. In particular, when the NLR cut-off value was set as ≥ 3, the difference was the most significant. Compared with patients in the low NLR group, those in the high NLR group had statistical differences in the number of lesions, preoperative hemoglobin level, preoperative glutamate transaminase, and preoperative absolute lymphocyte count. Multivariate survival analysis showed that postoperative chemotherapy and preoperative peripheral blood NLR were independent risk factors affecting the PS of patients.
Change laws of peripheral blood NLR before and after operation
Due to the great range of removal of tumor tissues in operations, the tumor load decreased significantly, and the stimulating effect of tumor cells on the immune and inflammatory reaction was reduced, resulting in great changes of the NLR before and after operation. Researchers in NLR changes in patients that underwent radical resection of non-small cell lung cancer before and after operation found that the NLR of a patient 1 month after operation increased by over 0.27, and the DFS and OS of the same patient were significantly shorter than those whose NLR declined or increased by less than 0.27. They believed that the change of NLR from that before operation to that 1 month after operation could be used for the early evaluation of the effectiveness of tumor therapy[27].
It was found in the study that MM patients had a high NLR before operation, which increased significantly 1 week after operation. In particular, in the second week after operation, the absolute neutrophil count increased significantly while the absolute lymphocyte count declined, in the second month after operation, the NLR declined while the absolute neutrophil count and absolute lymphocyte count returned to those before operation, and at the last follow-up visit, the NLR returned to a high level while the absolute neutrophil count increased significantly and the absolute lymphocyte count declined significantly. Such change laws indicate that a high preoperative NLR suggests a poor prognosis in MM patients, which may be the result of the imbalance of inflammatory reaction between anti-tumor and pro-tumor effects[26]. An elevated NLR indicates that the neutrophils in an MM patient's blood increased while the lymphocytes decreased, resulting in an imbalance between the anti-tumor effect of lymphocytes and the pro-tumor effect of neutrophils, thus affecting the prognosis of tumor patients.
Changes of the immune status of MMBD patients before and after operation and its effect on prognosis
Cellular immunity and humoral immunity play a key role in the occurrence and progression of tumors, and the function and status of cellular immunity largely reflect the progress of tumors and the prognosis of patients. At present, the clinical application of anti-tumor cell immunotherapy based on the correlation between cellular immunologic function and status and tumors is being more and more applied to clinical practice. Correct judgment and evaluation of the cellular immunologic function of patients with malignant tumor play an important role in evaluating the development of disease and guiding clinical treatment. Multiple myeloma is characterized by immunologic dysfunction Recently, MM's immune injury has been considered as another tool to predict prognosis[27]. Long-term survival in MM patients may be the result of unique immunologic characteristics, the most important of which is the reduction of immunosuppression[28]. Lymphocytes are an important part of the body's immune system. They contain subsets of different functions, which can be roughly divided into T cells, B cells and NK cells. With the continuous deepening of studies on the cellular and humoral immune functions in MM patients, domestic and foreign studies have found that there are various defects in the immune system of MM patients, including quantity anomaly and functional defect of B cells, T cells, NK cells and DC cells, as well as abnormal regulatory Tregs[29–30].
NK cells are derived from hematopoietic stem cells, which have the characteristics of MHC non-restriction and kill tumor cells without being activated. Bernal et al.[31] found in their study that the number of NK cells in peripheral blood of MM patients increased while their activity declined. Jurisic et al.[32] proved in their study that the decline of NK cell activity in patients was related to disease progression and the degree of plasma cell infiltration.
T cells play a major role in the anti-tumor immune reaction of tumor patients, and regulate the immune reaction of body and maintain immune stability. CD4/CD8 ratio reflects the cellular immunologic function and status of the body. In particular, CD4 + T cells are mainly helper T cells (Th), being the main reaction cells in the immune reaction, and CD8 + T cells are mainly composed of cytotoxic T cells and inhibitory T cells, producing cytotoxic effects on target cells. T cell subset expression anomaly plays an important role in the pathogenesis of MM. Koike and Oken et al. have found in their studies that there is a decrease in CD4 + T/CD8 + T in MM patients, which breaks the immune balance of MM patients and weakens their existing anti-tumor functions[33–34]. Treg is a subset of T cells that control autoimmunity and have negative immune regulation function, which maintains the immune system stability of body together with Th1 and Th2. It is related to the immune tolerance and tumor immune escape mechanism [35–36]. In recent years, studies by domestic and foreign scholars have shown that the proportion of Th1 and Th2 in MM patients is lower than that in patients in the healthy control group, suggesting that both humoral and cellular immunity of MM patients are damaged to varying degrees[37]. Therefore, lymphocyte subsets and Th cells are of great significance in the prognostic evaluation of MM patients. Lymphocytes play a key role in cell-mediated anti-tumor immune reaction, and their amount reflects the degree of reaction of the host immune system.
Whether operations affect the immune status of MM patients has not been reported. Results of the paper showed that the lymphocyte percentage of MM patients was at a normal low level before operation, which declined significantly 1 week after operation, returned to that before operation 1 month after operation, and returned to a low level at the last follow-up visit. They suggest that operations did affect the immune status of MM patients. After the operation, the immune balance of MM patients was broken in a short period of time, making them in low immune status. However, as time went by, their immune status recovered spontaneously, and returned to that before operation about 1 month after operation. Therefore, for MM patients that underwent operations, adjuvant therapy to enhance their immunity may be given when necessary, so as to allow them to be in a sound immune status, which may be helpful to the overall treatment of MM patients. The correlation between such results and the timing of chemotherapy after operation needs further study.
Neutrophils play a multivariate role in tumor diseases, but its role in cancer has not been fully understood[38]. Neutrophils reflect the inflammatory state of tumor patients and play different roles in different stages of tumor diseases[39]. Neutrophils release reactive nitrogen species (RNS), reactive oxygen species (ROS) or proteases that promote the occurrence of tumors[40]. The nitric-oxide synthase (iNOS) or argininase1 (ARG1) released by neutrophils inhibits the anti-tumor reaction of CD8 + T lymphocytes[41] by weakening the immune system to promote tumor proliferation and stimulated by TGF-β, and promotes metastasis and diffusion by inhibiting the natural killing function and promoting tumor cell extravasation[42]. In view of the role of neutrophils in the occurrence and development of tumor diseases, some researchers believed that the increase of neutrophil count was one of the adverse prognostic factors of head and neck cancer[43].
Results of the paper showed that the neutrophils of MM patients were at a normal level before operation, which increased significantly 1 week after operation, returned to that before operation 1 month after operation, and was lower than that before operation at the last follow-up visit. In our opinion, patients were in the postoperative inflammatory reaction period 1 week after operation, so their neutrophils were at a high level at that time. However, as time went by, their immune status after operation recovered, and returned to that before operation about 1 month after operation. This may be a normal body reaction, but whether such reaction affects tumors needs further study. At the last follow-up visit, the tumor status of patients was improved and the level of their neutrophils declined over that before operation due to the application of treatment measures such as operations and chemotherapy.
To sum up, changes of peripheral blood NLR were strongly correlated to the changes of lymphocyte count and neutrophil count and, during an operation, the peripheral blood NLR increased while the neutrophil count elevated and the lymphocyte count declined. Such a law of elevation may be a normal reaction of the body and not clearly correlated with the prognosis of tumors. Peripheral blood NLR before and 1 month after operation may reflect the immune status of patients from one side, and can be used as one of the indicators to predict operative prognoses.
To some extent, the study was inadequate. Firstly, some of the 82 MM patients recruited for the study lacked the lymphocyte subset information at different time points due to the large time span of diagnosis and treatment and varying locations of follow-up visits. Secondly, there might be some errors in the results of the study due to different treatment regimens for patients during the treatment period. Thirdly, the detection of peripheral blood-related cells alone failed to fully reflect the immune status of body. So, the specific mechanism of MM-induced changes in the immune status of body still needs further study and analysis. Among the patients that underwent operations, the number of patients undergoing operations at different sites and by different means were limited, so the multivariate test was unfeasible, while the results of the univariate test did have errors.