The prognosis of PTCL is poor, either in first-and second-line therapy or salvage therapy. There is an urgent need to use accurate predictive models to classify patients at risk. Among all the previously reported indices, IPI and PIT are the most commonly used. It is worth noting that there is considerable overlap in the parameters used to establish the various models and that the patients need to be evaluated by imaging, examination, bone marrow, etc. . The operations are complex, and the establishments of these scoring models are not entirely based on PTCL, so their accuracy are questionable.
With the development of medical science in recent years, more and more attention had been paid to the study of tumor molecular mechanisms, especially in tumor micro-environment. Therefore, the research on PTCL has opened a new chapter.
Recently, a growing body of research has consistently shown that tumor-associated inflammatory response is a key determinant of prognosis in cancer patients . In previous retrospective studies, we found an association between increased serum Interleukin-10 levels and low survival and early recurrence in patients with PTCL . Interleukin-10 is involved in the body's inflammatory and immune responses and plays an important role in tumors and infections. It is mainly secreted by monocytes, activated T-cells, macrophages, certain tumor cells and so on. Thus, monocyte and macrophage systems are closely related to the prognosis of PTCL. About 2-9% of peripheral leukocytes are peripheral blood monocytes (PBMC), but only 40% of them are used for monocyte circulation, while 60% of monocytes migrate . However, some immature PBMC can differentiate into specialized, tissue-specific macrophages and Antigen-presenting cells (APC). Their differentiation directly determines their functions. The differentiated monocytes/macrophages (Mphi) plays a specific role in the cell mediated innate immunity against infection, immunoregulation, morphogenetic remodelling and malignancy or tissue repair [19-20]. Subsequently, macrophages respond to a wide range of chemokines and growth or differentiation factors such as CCL-2 and CSF-1 produced by tumors and stromal cells. VEGFA and EGF produced by Tumor-associated macrophages (TAMs) promote angiogenesis and tumor growth, respectively, which is consistent with the positive correlation between CD68 expression, vascular invasion and tumor length . Macrophages are remarkably plastic. Depending on the stimulus that activates them, they can polarize to either type M1(causing an anti-tumor response) or type M2(causing tumor growth and progression). It had been demonstrated that the growth and survival of malignant T-cells depend on alternatively activated (M2) macrophages in the micro-environment and that the growth of alternatively activated (M2) macrophages were influenced by TAMs . Yingming Zhu et al. found that LMR was associated with TILs/TAMs ratio, and that low LMR had worse OS in patients with esophageal squamous cell carcinoma . It suggests that a systemic inflammatory response may reflect concurrent focal inflammation in the tumor.
D.Iacono et al. retrospectively analyzed 165 patients with advanced melanoma. The severity and prognosis of the disease were assessed. The decrease of LMR suggests short OS and more distant metastatic sites in malignant melanoma . Wang et al. reported 355 cases of diffuse large B-cell lymphoma (DLBCL). In the low LMR group, PFS and OS were shorter and M2-TAM content was higher. These results suggested that weak anti-tumor immunity may be an adverse prognostic factor for aggressive lymphoma, identified in high-risk patients . Thus, lymphocyte counts, monocyte counts, and LMR surrogate markers of tumor micro-environment had been reported as prognostic factors for B cell lymphoma[24-26]. Similarly, recent studies had shown that both lymphocyte counts and monocyte counts could predict the clinical outcome of T-cell lymphomas[27-28]. And patients with T-cell lymphomas after autologous peripheral hematopoietic stem cell transplantation had longer OS and PFS with autograft lymphocyte-to-monocyte ratio(A-LMR) greater than or equal to 1. Compared with patients with A-LMR less than 1, the five years OS rate was 87% to 26% , and the five years PFS rate was 72% to 16% , significant difference . But in our study, patients with LMR less than or equal to 1.68 had a median OS and significantly worse CR rate for treatment than patients with LMR greater than 1.68 (5 months vs. 28.5 months; 14.2% vs. 45%) . The main reasons for this difference include: first, in Luis F et al.'s study, they examined autograft lymphocyte-to-monocyte ratio(A-LMR), whereas our study examined LMR in patients'peripheral blood at the time of initial diagnosis; second, they included only 109 patients, we included 347 patients; third, they chose patients with T- cell lymphomas, and we included peripheral T-cell lymphomas, with different baseline characteristics.
Megakaryocytogenesis is a process in which megakaryocytes (MK) proliferate, differentiate and mature from pluripotent hematopoietic stem cells (HSC), while platelets are formed from mature MK fragments. The average platelet count in humans is between 150×109 and 400×109 per liter, but over time, the number of individual platelets remains the same. Platelets mainly participates in the organism haemostasis and the thrombosis. In recent years, there are increasing evidences that platelets and tumor cells have significant cross-communication, suggesting that they play an important role in the progression of malignant tumors, the occurrence of tumor-associated local inflammation, and cancer-associated thrombosis. On the one hand, tumors can affect the RNA profile of platelets, the number of circulating platelets and their activation status. On the other hand, tumor-induced platelets contain a large number of active biomolecules, including platelet-specific and circularly ingested biomolecules that are released upon activation of platelets and are involved in the development of malignant tumors. Tissue factor (TF) has a direct pro-inflammatory effect by inducing the production of reactive oxygen species . Thus, platelets are directly involved in the initiation of inflammatory responses (clotting, monocyte recruitment, activation, and matrix remodeling) by inducing additional adhesion molecules, MMPs, tissue-type plasminogen activators, and cytokines (such as MCP-1) in endothelial cells . Platelets store and release CXCL12 (SDF-1), which controls the differentiation of hematopoietic progenitors into endothelial cells or macrophage-foam cells. CXCL12 binds CXCR4 and CXCR7 and regulates the functions of monocyte/macrophages. M Chatterjee et al. found that platelets and platelet-macrophage aggregates increased in peritoneal fluid following peritonitis induction in mice in vivo. Compared with peripheral blood, the relative surface expressions of CXCL12, CXCR4 and CXCR7 in infiltrated monocytes were also enhanced. Moreover, platelet CXCL12 and recombinant CXCL12 participate in the enhancement of specific induction of monocyte chemotaxis through CXCR4. Under static and dynamic arterial flow conditions, the adhesion of monocytes to the surface of immobilized CXCL12 and activated platelets rich in CXCL12 is mediated mainly through CXCR7, and is counter-regulated by neutralizing platelet-derived CXCL12. In the co-culture experiment with platelets, monocytes were mainly differentiated to CD163+ macrophages, and CD163+ macrophages weakened after blocking antibodies to CXCL12 and CXCR4/CXCR7. Therefore, platelets-derived CXCL12 can regulate mononuclear-macrophage functions through different combinations of CXCR4 and CXCR7, suggesting that it plays an important role in platelet aggregation in local inflammatory responses .
Platelet activation plays an important role in tumor-associated immune thrombosis and multiple metastasis. Activated platelets were known to secrete a range of inflammatory chemokines that activate inflammatory signaling pathways in white blood cells, including PAF, RANTES, CCL3, CXCL1, CXCL4 (platelet factor 4), and CXCL7 [35, 36]. Serotonin (5-hydroxytryptamine) is another platelet-releasing product that may affect monocyte function. Monocytes exposed to 5-hydroxytryptamine showed increased NF-κB activation, increased cytokine production induced by LPS, and decreased apoptosis, possibly due to changes in BCL-2 or MCL-1 expression . In the past few decades, a large number of clinical studies have shown that daily aspirin can reduce the incidence, metastasis and mortality of tumors, especially for colorectal cancer . Recently, Guillem Lobat P and his collaborators demonstrated in an immunodeficiency mouse model that low-dose aspirin reduces the metastasis of lung cancer by avoiding the enhanced pro-aggregation effect caused by platelet-tumor cell interaction . These clinical studies have fully confirmed that platelets are closely related to the occurrence and development of tumors.
In conclusion, since both host immunity and tumor micro-environment are closely related to the occurrence, development and metastasis of tumor, the combination of lymphocyte count, monocyte count and platelet count can better reflect the prognosis of tumor. LMR had been studied in many different disease settings, had been widely discussed, and had been found to predict esophageal cancer, melanoma, Hodgkin's lymphoma, multiple myeloma, and DLBCL [13,23,40-42]. However, it has never been discussed in PTCL. Platelet counts and monocyte counts had been shown to be associated with sepsis, pulmonary embolism [43-44], and so on, but no correlation between platelet counts and monocyte count ratios and tumors has been previously reported. We analyzed 347 patients with primary PTCL and found that the patients with low LMR ratio and low PMR ratio had worse response to treatment and shorter survival time. The difference were significant in low-to-moderate-risk patients with an IPI score of 0-2 and in high-to-moderate-risk patients with an IPI score of 3-5. In multivariate tests, LMR ≤ 1.68 and PMR ≤ 300 were independent risk factors for OS shortening. By integrating reduced LMR and PMR to produce a "PBS" model, newly diagnosed PTCL patients can be divided into three risk groups. Specifically, patients in the low-risk group had no abnormal blood cells and had a 3-year survival rate of 43.4% , while those in the high-risk group had a 3-year survival rate of 13.1% .
Our study still has some limitations. Firstly, the retrospective study may be biased in the selection of patients. Secondly, the dynamic changes of patients during treatment did not taken into account during analysis. Third, our sample size is relatively small and lack of cytogenetic data. Another issue is the cut-off value of LMR/PMR used in clinical practice. In the past and in our study, the ROC curve based on survival was used to determine the optimal cut-off value, indicating that there was inconsistency between the centers. Therefore, further exploration and prospective trials with larger samples are needed in the future and the PBS model we established also needs further verification.