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Recent clinical studies have found that there are still a large number of patients who do not respond to immune checkpoint inhibitors (ICIs). Improving immunotherapy response in ccRCC patients is an urgent clinical need. Targeting different components of the tumor immune microenvironment becomes a breakthrough point for overcoming the immunotherapy resistance and optimizing therapeutic strategies in advanced ccRCC. Several novel immunotherapeutic strategies are currently under clinical investigation, including targeting other co-inhibitory and co-stimulatory molecules, modified cytokine therapies, small-molecule immunomodulators, targeting immune metabolism, and cancer vaccines, each of which target different immunomodulatory pathways in the tumor immune microenvironment for the treatment of ccRCC. In this paper, we provide an overview of the current challenges faced by immunotherapy for advanced ccRCC and review novel immunotherapy strategies based on the tumor immune microenvironment.
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Objective To investigate expression and suppressive function of CD39 + regulatory T cells (Treg) in kidney transplant recipients.Method Thirty recipients of first kidney transplants were treated with tacrolimus,mycophenolate mofetil and prednisone.Within 28 days posttransplantation,there were 14 patients subject to acute rejection (AR group),and the rest 16 patients had no episodes of acute rejections (NR group).Twelve healthy volunteers served as healthy controls (HC group).We collected peripheral blood from the three groups and separated PBMC by density gradient centrifugation,and sorted Tresp,CD39-Treg and CD39+ Treg by flow cytometry.We next analyzed the ratio of CD39 + Treg/CD4+ T cells.ELISA was used to determine the suppressive ability of CD39-Treg and CD39+ Treg on secretion of IFN-γ and IL-17 by Tresp.Results The ratio of CD39 + Treg/CD4 + T cells in AR group was significantly reduced as compared with HC group and NR group (P＜0.05).In HC group and NR group,the secretion of IFN-γ and IL-17 by Tresp was suppressed significantly (P＜0.05) by CD39+ Treg.CD39Treg could suppress secretion of IFN-γ but not IL-17 production by Tresp.CD39+ Treg in AR group AR could suppress the secretion of IFN-γ significantly (P＜0.01),but not to IL-17 production.Conclusion CD39+ Treg have important immunoregulation function.The relative amount of CD39+ Treg was reduced and their regulatory function was impaired in patients with acute rejection.
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Objective To study the In vitro expansion of human CD8+ CD28- suppressor T cells and their immunological regulatory effect.Methods Human CD8 + CD28- suppressor T cells were expanded in vitro driven by the combination of cytokines and allogeneic antigen presenting cells (APCs).Flow cytometry was used to assess the development of CD28- subpopulation.Expanded CD8+ CD28- T cells were isolated by immunomagnetic microspheres and then added as third part modulators into mixed lymphocyte culture to assess their immunological regulatory characteristics.Results The combination of cytokines included IL-2,IL-7 and IL-15 and allogeneic APCs could increase the portion of CD8 + CD28- T cell subtype,and expansion fold of CD8+ CD28- T cell subtype was significantly increased as compared with others (P＜0.05).Expanded CD8+ CD28- T cells could suppress the proliferation of CD4+ T cells stimulated by allogeneic APCs.Moreover,this suppression had antigen specificity.Conclusion Human CD8 + CD28- suppressor T cells can be in vitro expanded in large amounts driven by the combination of cytokines and allogeneic APCs.Expanded CD8 + CD28- T cells in this study have antigen specific regulatory characteristics.
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Objective To explore the impact of induction therapy with anti-lymphocyte agents on long-term survival of kidney transplantation.Methods 271 recipients of first cadaveric kidney transplants were treated with tacrolimus,mycophenolate mofetil and prednisone.110 patients of them received induction therapy with anti-thymocyte globulin(ATG group),88 patients received Basiliximab(Bax group),and the remaining 73 patients did not receive induction therapy(control group).The data of AR,DGF,CMV infection,and 1- 3- 5-year patient/allograft survival rate in three groups were retrospectively during a follow-up period of 1 to 5 years postoperatively.Results Within 6 months after operation,the incidence of AR in control group,ATG group and Bax group was 17.8 %(13/73),9.1 %(10/110)and 10.2 %(9/88)respectively.The incidence of AR in ATG group and Bax group was significantly lower than in control group (P<0.05).There was no significant difference in incidence of DGF and CMV infection among three groups.The 1-,3- and 5-year allograft survival rate postoperation in ATG group and Bax group was 95.5 %,90.9 %,87.3 % and 93.2 %,87.5 %,83.8 % respectively,which was significantly higher than in control group(87.7 %,80.8 % and 75.3 %,P<0.05).Conclusion Induction therapy with anti-lymphocyte agents may reduce the early incidence of AR and prolong long-term allograft survival significantly.
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Objective To investigate the dynamic expression and clinical significance of toll-like receptor 4(TLR4)/CD80 in patients before and early after renal transplantation. Methods Thirty-two patients who received renal transplantation were enrolled in his study. All of them were primary recipients, and the level of panal reactive antibody less than 1%. The expression of TLR4 and CD80 in CD14, positive monocyte of peripheral blood from atients on the 1st, 4th, 7th, 14th, 21st, 28th and 35 th days after transplantation were measured by three-color fluorescent taining flow cytometry. The pa-tients were divided into rejection roup(7 cases) and non-rejection group(25 cases) according to rejec-tion episode record within 2 weeks. Normal control group(10 cases) enrolled healthy adult volunteers. Diagnosis of acute rejection depended on clinical symptoms, lab test, color doppler onography and re-nal biopsy. Results Before ransplanstation, the ressions of TLR4 and CD80 were (8.03± 0.84)% and (0.85±0.31)% in rejection group, (6.14±0.85)% and (0.84±0.39)% in non-rejec-tion group, (6.37±0.56)% and (0.85±0.35)% in normal control group. The expression of TLR4 of rejection group was higher than those of non-rejection group and normal control group(P<0.01). The expressions of CD80 of 3 groups had no significant difference(P=0.995). After ransplanstation, the expressions of TLR4 and CD80 increased to (16.50±1.02)% and (7.82±1.66)% in rejection group, (11.60±0.98)% and (2.26±0.96)% in non-rejection group at the 4th day, and reached the peak levels at the 7th day: (36.40±4.86)% and (9.53±1.97)% in rejection group, (22.70± 3.45)% and (1.87±0.72)% in non-rejection group, then displayed downtrend, rejection group de-creased to (7.10±0.82)% and (0.87±0.57)% at the 35th day, non-rejection group decreased to (7.20±0.76)% and (0.81±0.37)% at the 21st day. Compared with non-rejection group, rejection group showed higher peak expression value of TLR4/CD80 (P<0.01) and longer lasting time. Con-clusions The high expression of TLR4 may increase the risk of acute rejection. The up-regulated TLR4/CD80 levels early after renal transplantation may ontribute to the happeness of acute rejection.
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0.05). In group B,the serum creatinine levels of cases treated with ulinastatin at 1,3,7,10 and 14 days after renal transplantation were (372.6? 128.1 ),(278.4?38.9),(145.9? 47.2 ),(133.2?39.8),(128.0?30.6)?mol/L,respectively;the values of controls were (496.3?125.6),(364.7?60.2),(196.2?36.8),(161.4?41.5),(149.8? 33.5 )?mol/L,respectively ( P