Predictive Value Of Tumor Immune Microenvironment Factors In Improving IPI-related Risk Stratification Of Aggressive B Cell Lymphoma

Although past decade has witnessed remarkable improvement in the treatment of hematological malignancies,non-Hodgkin lymphoma(NHL)remains an important cause of morbidity and mortality with increasing incidence worldwide,and over half of NHL are categorized as aggressive B cell lymphomas.Aggressive B cell lymphomas include diffuse large B cell lymphoma(DLBCL),lymphoblastic B cell lymphoma(LBL),Burkitt lymphoma(BL),mantle cell lymphoma(MCL),and other B cell lymphoma entities.As the largest group among aggressive B cell lymphomas,diffuse large B cell lymphoma(DLBCL)can be further classified into at least two molecular subtypes: germinal center B cell like subtype and non-germinal center B cell subtype according to characteristics of gene expression profile or immune phenotypes.The clinical course and prognosis of different subtypes of DLBCL and other aggressive B cell lymphomas are quite variable due to different intrinsic mechanisms.In recent years,combination of chemotherapy,antibody-based target therapy and radiation therapy has improved the survival of aggressive B cell lymphomas significantly,however,relapse and refractory diseases still presents a major treatment challenge and poor clinical outcome.Multiple risk stratification systems have been developed to identify cancer patients with a worse prognosis.The International Prognostic Index(IPI),based on clinical parameters such as age,LDH,number of extranodal sites,Ann Arbor stage,and ECOG performance status,has been one of the most commonly used tool to predict the therapeutic response and prognosis of patients with aggressive NHL in the pre-rituximab era.And new versions of IPI including revised IPI(R-IPI)and NCCN-IPI have been reported to demonstrated superiority to the previous standard IPI score system since the introduction of a combination of rituximab plus chemotherapy.Tumor microenvironment of lymphoma plays an important role in the development and progression by interaction of tumor cells and immune system and influences prognosis and response to therapy.For example,the immune checkpoint pathways,especially for PD-1/PD-L1 pathway have been reported to mediate tumor infiltrating cytotoxic T lymphocytes exhaustion,and blockade of PD-1/PD-L1 pathway with antibodies was believed to be a highly promising therapy for various advanced tumors including lymphomas.In addition,the components of a differential white cell count(WBC-DC),systematic inflammatory and metabolic markers such as serum albumin(ALB),lactate dehydrogenase(LDH),?-2 microglobulin(?2MG),and iron in peripheral blood have been reported as available and economical parameters for prognostic categorization of malignant diseases including solid and hematological malignancies.However,the relationship between immune cell status of tumor microenvironment and risks based on the most commonly used score models(IPI,R-IPI,NCCN-IPI)is not clear.In this study,we evaluated the density of CD4,FOXP3,CD8,CD68,CD163 positive immune cells,and PD-1,PD-L1 expression in 127 cases of aggressive B cell lymphomas as well as the systemic immune-inflammatory cell counting,and serum levels of ALB,LDH,?2MG to analyze the correlation of these immune related factors and risk stratification of patients with aggressive B cell lymphoma.The aim is to investigate the predictive value of tumor immune microenvironment as well as systematic inflammatory and metabolic factors in risk stratification of patients with aggressive B cell lymphomas.Methods:One hundred and twenty-seven cases of aggressive B cell lymphomas diagnosed between 2014 and 2015 were enrolled into this study.Immunohistochemistry staining of CD4,FOXP3,CD8,CD68,CD163,PD-1 and PD-L1 were performed in paraffin embedded lymphoma tissue sections of patients.Clinicopathologic features including age,sex,histological classification,sites of involvement,Ann Arbor stage,B symptom,ECOG performance status,infiltrating immune cells,expression of PD-1 and PD-L1,white blood cell differential count,serum LDH,serum iron,serum albumin and serum beta2 microglobulin were evaluated for their roles of risk stratification on aggressive B cell lymphomas.Eleven factors were identified for further estimation of risk stratification using ANOVA,Chi-Square,and multinominal logistic regression analysis.The difference of concordance rate utilizing the above factors with or without Ann Arbor stage were compared with paired T tests.Results:Significant differences of 11 factors(age,Ann Arbor stage,B symptom,ECOG performance status,infiltrating CD8+ T cells,expression of PD-L1,absolute count of monocytes in blood,serum LDH,serum iron,serum albumin and serum beta2 microglobulin)were observed between subgroups of patients stratified by at least two of three risk stratification methods(IPI,revised IPI(R-IPI),and NCCN-IPI)models(p?0.05).There were high concordance rates(83%-100%)of predicted risk stratification by multinomial logistic regression analysis with the above 11 factors.And there was no significant difference of the estimated risk stratification results when utilizing the above clinicopathologic factors with or without consideration of Ann Arbor stages.Conclusions:The results in our study proved the importance of immune microenvironmental factors in risk stratification of aggressive B cell lymphomas,and we also demonstrated a potential economical and convenient tool aiding in the risk stratification of aggressive B cell lymphomas using 11 parameters including age,Ann Arbor stage,B symptom,ECOG performance status,infiltrating CD8+ T cells,expression of PD-L1,absolute count of monocytes in blood,serum LDH,serum iron,serum albumin and serum beta2 microglobulin.In addition,our results suggest the feasibility for an earlier evaluation on the risk stratification of aggressive B cell lymphoma patients before finishing examination for clinical staging.Further researches for validation of the role of Immune microenvironment factors in predicting IPI related risk stratification of aggressive B cell lymphoma will be needed in the future.