The Correlation Of TIPE2 Expression With Tumor Microenvironment And The Prognosis Of Patients With Colorectal Cancer

Background Colorectal cancer(CRC),according to the latest statistics,affects more than 1.9 million people annually and causes more than 900,000 deaths each year.TIPE2(TNFAIP8L2)is a member of the tumor necrosis factor-alpha-inducible protein8(TNFAIP8/TIPE)family and is preferentially expressed by leukocytes.It was discovered in 2008 in an animal model of experimental autoimmune encephalomyelitis in mice.TIPE2 is expressed at high levels in immune cells such as macrophages and lymphocytes.Increasing evidence suggests that TIPE2 is a novel negative regulator for maintaining immune homeostasis and is involved in the maintenance of both the host intrinsic and adaptive immune responses.Currently,TIPE2 is reported to be involved in the development of a variety of diseases,such as autoimmune diseases,diabetic nephropathy,atherosclerosis,and tumors,and is closely associated with immune regulation and tumorigenesis.It has long been recognized that the tumor microenvironment(TME)plays a crucial role in the biological behavior of cancer.Among them,CD8+ T cells are playing an important role in innate and adaptive immune defense mechanisms.CD20 has been widely used in assessing the degree of inflammatory infiltration in different tumors.CD66b+ tumor-associated neutrophils(TAN)are closely associated with the development and prognosis of some tumors.However,the role of TIPE2 in the development of colorectal tumors and its relationship with tumor immunity are not fully understood.In this study,we investigated the expression level of TIPE2 in colorectal tumor tissues and normal tissues adjacent to cancer,its prognostic value,and its relationship with corresponding clinicopathological data.It revealed that overexpression of TIPE2 may have a potentially important relationship with tumor immune infiltration and poor prognosis of patients.ObjectiveThe symptoms of early CRC are not obvious and do not receive enough attention from patients,thus delaying the diagnosis and treatment of the disease.By the time of definite diagnosis,the disease is often already in the middle and late stages,with multiple organ infiltration and distant metastases,resulting in loss of opportunity for radical resection surgery and poor prognosis.The molecular markers commonly used in clinical diagnosis of CRC include carcinoembryonic antigen(CEA),Carbohydrate antigen199(CA199),inflammatory markers Neutrophil-lymphocyte ratio(NLR)and Platelet-lymphocyte ratio(PLR).However,all of these markers face the problems of relatively insufficient specificity and sensitivity,and therefore are often used as monitoring the recurrence of CRC.Therefore,it is necessary to further investigate the pathogenesis of CRC and seek more stable and better specific molecular markers to improving the treatment of CRC and improving the survival of CRC patients after surgery.Methods(1)The relationship between the expression of TIPE2 in colorectal cancer and tumor immune infiltration was analyzed using the TCGA database.(2)In cancer tissues and adjacent tissues from surgically resected specimens of 110 CRC patients,the expression of TIPE2 was examined using immunohistochemistry,and the expression of CD8,CD20,and CD66 b in cancer tissues and adjacent tissues was also examined.The scores were based on the expression.(3)The median immunohistochemical scores of TIPE2,CD8,CD20,and CD66 b and the normal range of clinical indices were used as cutoffs to group patients.Survival profiles for different indicators were analyzed and plotted using the Kaplan-Meier procedure as a way to analyze the relationship between patient outcomes and each indicator.(4)The TIPE2,CD8,CD20 and CD66 b immunohistochemical scores were integrated with the clinical indicators of the corresponding patients.And LASSO regression and COX analyses were used to screen out the independent risk factors for the overall survival of the patients.(5)Nomogram of overall survival of CRC patients were constructed based on the screened independent risk factors to predict the survival rate of CRC patients at 1,3,and 5 years,and validated using clinical calibration curves and ROC curves.Results(1)Immunohistochemical results indicated that the expression of TIPE2,CD8 and CD20 was higher in cancer tissues,and the expression of CD66 b was lower in cancer tissues.(2)Survival analysis showed that in colorectal cancer tissues,CRC patients with high CD8 and CD20 expression were in a relatively worse state of survival,and CRC patients with high TIPE2 expression were in a relatively better state of survival;in adjacent normal tissues,CRC patients with high CD8,CD20 and CD66 b expression were in a relatively worse state of survival;CRC patients with high TIPE2 expression were in a relatively better state of survival.Among other clinical indicators,hypofractionation,T4 stage,N2 stage,white blood cell count <3.5*10^9/L,neutrophil count <1.8*10^9/L,CEA >5ng/m L and CA199 >27μg/m L indicated that CRC patients faced poorer overall survival.(3)After LASSO regression,univariate and multivariate COX regression analyses,TIPE2 and differentiation degree in cancer tissues were independent protective factors for overall survival(OS)in colorectal cancer patients,and CD8,N-stage and CA199 in adjacent normal tissues were independent risk factors for OS in colorectal cancer patients.(4)Based on the screened independent protective and risk factors for OS,nomogram was constructed to predict the survival probability of CRC patients at 1,3,and 5 years.The AUCs at 1,3,and 5 years were 0.642,0.691,and 0.690,respectively.The ROC curves and clinical calibration curves indicated that the constructed prediction model had good predictive ability.ConclusionCRC patients with high expression of TIPE2 have a better prognosis.CRC patients with high expression of CD8 and CD20 were in a relatively worse state of survival.And CRC patients with high expression of CD66 b in adjacent normal tissues were in a relatively worse state of survival.TIPE2 combined with immune cells such as CD8,CD20 and CD66 b in the TME can be used as a biomarker to predict disease progression and prognosis in colorectal cancer patients.