T Cell Response to Embryonal Carcinoma F9 Cells: Induction and Characterization of T Cell Receptor αβ+ Double-negative Cytotoxic T Lymphocytes

We investigated the mechanism of T cell response to marine embryonal carcinoma F9 cells. Thy-1⁺, CD4⁻, CD8⁻ (double-negative) cytotoxic effector cells were induced in spleen cells obtained from immune A.BY mice to F9 cells, and the cytotoxic activity was major histocompatibility complex (MHC)-unrestricted. Furthermore, CD4⁺ T cells were essential for the induction of double-negative cytotoxic T lymphocytes directed to F9 cells. Most of the double-negative cytotoxic T lymphocyte lines obtained by long-term culture of the effector cells had CD3 molecule and T-cell receptor β chain on their cell surface, and the CDS molecule was found to be involved in target cell recognition. The T cell receptor αβ⁺ double-negative cytotoxic T lymphocyte line (2A5) also lysed various tumor cells in a non-MHC-restricted manner, but did not lyse concanavalin A-stimulated blasts of 129 strain, from which F9 cells had originated. These results indicate that T cell receptor αβ⁺ double-negative cytotoxic T lymphocytes induced by F9 cells recognize a common antigen(s) expressed on F9 cells and other tumor cells but not minor histocompatibility antigens.     

Increased Frequency of Foxp3+ Regulatory T Cells in Mice with Hepatocellular Carcinoma

The CD4+CD25+ regulatory T cell (Treg) is a special kind of T cell subset. Studies have showed that Tregcells are involved in a number of physiological processes and pathologic conditions such as autoimmune diseases,transplantation tolerance and cancer. Tregs with unique capacity for immune inhibition can impair anti-tumourimmunity and help tumor cells to escape from immune surveillance. The aim of our study was to investigatewhether Tregs are involved in hepatocellular carcinoma (HCC). A BABL/C mouse with HCC in situ model wasestablished to evaluate the Treg existence in carcinoma tissues and the changes of Tregs in spleen using flowcytometry and immunohistochemistry methods. Granzyme B expression in carcinoma tissues was analyzedby immunohistochemistry to investigate the tumor local immune status.The proportion of CD4+CD25+/CD4+spleen lymphocytes of tumor bearing mice (18.8%±1.26%) was found to be significantly higher than that innormal mice (9.99%±1.90%) (P<0.01 ). Immunohistochemistry of spleen tissue also confirmed that there wasan increase in Treg in tumor-bearing mice, while in carcinomas it showed Treg cells to be present in tumorinfiltrating lymphocyte areas while Granzyme B was rarely observed. Anti-tumour immunity was suppressed,and this might be associated with the increase of Tregs. Our observations suggest that the CD4+CD25+Treg/CD4+ proportion in spleen lymphocytes can be a sensitive index to evaluate the change of Tregs in hepatocellularcarcinoma mice and the Treg may be a promising therapeutic target for cancer.     

Identification of promiscuous HPV16‐derived T helper cell epitopes for therapeutic HPV vaccine design

Cervical carcinoma and several other human papillomavirus (HPV)‐induced malignancies are a global public health problem, thus novel treatment modalities are urgently needed. Immunotherapy is an attractive option for treatment of HPV infection and HPV‐mediated premalignant and malignant lesions. However, previous approaches—focusing on the induction of cytotoxic CD8+ T cells (CTLs)—have as yet not yielded clinical successes. Since CD4+ T cells have been shown to be crucial for the induction and maintenance of CTL responses, and more recently to be also important for direct anti‐tumor immunity, human leukocyte antigen (HLA) class II‐restricted epitopes are intensively investigated to improve the efficacy of peptide‐based HPV immunotherapy. We here present an approach to identify promiscuous HPV16‐derived CD4+ T helper epitopes, which are capable of inducing T cell immunity in a large proportion of the population. To this end, we combined HLA class II epitope prediction servers with in vitro immunological evaluation to identify HPV16 E2‐, E5‐, E6‐, and E7‐derived CD4+ T cell epitopes. Candidate selected HPV16‐derived epitopes were found to be restricted by up to nine HLA‐DR molecules. Furthermore, they were found to induce frequent and robust HPV16 peptide‐specific Th1 responses in healthy donors, as monitored by interferon (IFN)‐γ ELISPOT and cytokine secretion assays. Moreover, these selected peptides also induced specific IFN‐γ T cell responses in blood from HPV16+ CIN2/3 and cervical carcinoma patients. We thus conclude that the identified T helper epitopes are valuable candidates for the development of a comprehensive therapeutic HPV vaccine.     

维吾尔族妇女局部晚期宫颈鳞癌外周血T细胞亚群与临床特征和预后关系

目的 观察新疆地区维吾尔族局部晚期宫颈鳞癌患者外周血T细胞亚群与临床特征、预后的关系。方法 选择2015-2018年间新疆医科大学附属肿瘤医院经组织病理证实的ⅡB-ⅣA期宫颈鳞癌患者185例,回顾性分析外周静脉血T细胞亚群与临床特征及预后的关系。结果 CD⁺₄T细胞、CD⁺₈T细胞、CD⁺₄/CD⁺₈T细胞比值与临床分期、肿瘤最长径、体质量指数(BMI)有关(均P<0.05)。国际妇产科协会(FIGO)分期越晚、最长径越大、BMI越高,CD⁺₈T细胞越高,CD⁺₄T细胞、CD⁺₄/CD⁺₈T细胞比值越低;淋巴结转移者,CD⁺₄T细胞减低。单因素分析结果显示FIGO分期、年龄、淋巴结转移、肿瘤最长径、BMI、CD⁺₄T细胞、CD⁺₈T细胞、CD⁺₄/CD⁺₈T细胞比值及治疗方式是影响局部晚期宫颈鳞癌患者总生存(OS)的重要因素;多因素分析结果显示BMI、治疗方式、CD⁺₄T细胞及肿瘤最长径是影响患者OS的独立预后因素(均P<0.05)。结论 维吾尔族宫颈癌患者外周血T细胞亚群水平失调,CD⁺₄T细胞、CD⁺₈T细胞、CD⁺₄/CD⁺₈T细胞比值与宫颈癌FIGO分期、肿瘤最长径、BMI有关,CD⁺₄T细胞还与淋巴结转移相关。BMI、治疗方式、肿瘤最长径及CD⁺₄T细胞是影响患者OS的独立预后因素。     

Relationship between T cell subsets in peripheral blood and clinical characteristics and prognosis of Uygur women with advanced cervical squamous cell carcinoma

Objective To observe the relationship between peripheral blood T cell subsets and clinical characteristics and prognosis of Uygur women with advanced cervical squamous cell carcinoma in Xinjiang. Methods A total of 185 patients pathologically diagnosed with stage ⅡB-IVA cervical squamous cell carcinoma admitted to Cancer Hospital Affiliated to Xinjiang Medical University from January 2015 to December 2018 were selected. The relationship between T cell subsets in peripheral venous blood and clinical characteristics and prognosis was analyzed. Results CD⁺₄ T cells, CD⁺₈ T cells and CD⁺₄/CD⁺₈ T cell ratio were significantly correlated with clinical stage, tumor diameter and body mass index (BMI)(all P<0.05). The later Federation International Association of Gynecology and Obstetrics (FIGO) tumor stage, the larger the tumor diameter, the higher the BMI, and the higher the CD⁺₈ T cells and the lower the CD⁺₄ T cell and CD⁺₄/CD⁺₈ T cell ratio. The count of CD⁺₄ T cells was decreased in patients with lymph node metastasis. Cox’s univariate analysis showed that FIGO stage, age, lymph node metastasis, tumor diameter, BMI, CD⁺₄ T cells, CD⁺₈ T cells, CD⁺₄/CD⁺₈ T cell ratio and treatment methods were the important factors affecting the overall survival (OS). Multivariate analysis showed that BMI, treatment method, CD⁺₄T cells and tumor diameter were the independent prognostic factors affecting OS (all P<0.05). Conclusions The level of T cell subsets in peripheral blood of Uygur cervical cancer patients is out of balance. CD⁺₄T cells, CD⁺₈ T cells and CD⁺₄/CD⁺₈ T cell ratio are associated with FIGO stage, tumor diameter and BMI, and CD⁺₄T cells are correlated with lymph node metastasis. BMI, treatment method, tumor diameter and CD⁺₄ T cell are the independent prognostic factors affecting the OS of patients with cervical cancer.     

程序性死亡配体1、肿瘤浸润淋巴细胞、FoxP3+调节性T细胞在非小细胞肺癌中的表达及意义

[目的]检测程序性死亡配体1(programmed death ligand 1,PD-1)、肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)和叉头转录因子P3(forkhead box P3,FoxP3)在非小细胞肺癌(non-small celllung cancer,NSCL...     

Cytotoxic Activity of CD4+ T Cells against Autologous Tumor Cells

The ⁵¹Cr-release assay is mostly applied to detecting the cytotoxic activity of CD8⁺ T cells, and little is known about the activity of CD4⁺ T cells. Therefore, the correlation between the cytotoxic activity of CD4⁺ or CD8⁺ T cells and the incubation period with autologous tumor cells was analyzed by two methods. The incubation periods were 4 and 20 h (4 h and 20 h assay) for the ⁵¹Cr-release assay. Eight pairs of tumor cells and T cells were assayed. T cells were fractionated into CD4⁺ and CD8⁺ T cells by using magnetic beads and panning methods, and those cells were activated by culture with recombinant interleukin-2 and immobilized anti-CD3 monoclonal antibody. In 6 out of 8 cases, no cytotoxic activity of CD4⁺ T cells was detected by the 4 h assay, whereas cytotoxic activity was detected in all cases in the 20 h assay. The cytotoxic activities in 20 h assay of CD4⁺ T cells were increased 67-fold in comparison with the activities in 4 h assay (range: 5–197). In the case of CD8⁺ T cells, cytotoxic activities were detected in 6 out of 8 cases in the 4 h assay. The lytic unit ratio of CD4⁺ and CD8⁺ T cells was calculated as 1.5 in the 20 h assay (range: 0.2->7.2) versus 0.4 in the 4 h assay (range: < 0.1–1.3). Cytotoxic activities in colorimetric assay using Crystal Violet with a 24 h incubation were similar to those in the 20 h ⁵¹Cr-release assay in all eight cases. These results indicate that CD4⁺ T cells have cytotoxic activity as strong as that of CD8⁺ T cells towards autologous tumor cells.     

调节性T细胞诱导肿瘤免疫耐受的机制

调节性T细胞(Treg)是一类免疫抑制性T辅助(Th)细胞.研究表明,Treg可在肿瘤细胞分泌的趋化因子CCL22作用下大量募集于肿瘤周围,分泌或表达免疫抑制性的细胞因子和受体,形成以Th2型免疫为主的微环境,引导宿主免疫耐受.通过抗体等药物降低Treg数量和活性后可打破肿瘤免疫耐受,抑制肿瘤的发生和转移.     

Mediation of in vivo Tumor-neutralizing Activity by Lyt-2+ as Well as L3T4+ T Cell Subsets*1

The present study reexamines the cell surface nature of T cells mediating in vivo protective tumor immunity with the use of anti-L3T4 and -Lyt-2 antibodies. C3H/HeN mice hyperimmune against syngeneic MH134 hepatoma or MCH-1-A1 fibrosarcoma were prepared by intradermal (id) inoculation of viable tumor cells followed by surgical resection of the tumor and by repeated challenges with viable tumor cells. Spleen cells from these mice were fractionated into L3T4⁺ or Lyt-2⁺ T cell subset by treatment with anti-Lyt-2 or -L3T4 antibody plus complement (C). Winn assays performed by utilizing such fractionated T cells have revealed that both L3T4⁺ and Lyt-2⁺ T cell subsets from hyperimmune mice produced complete tumor protection. Flow microfluorometry study illustrated that the treatment with anti-L3T4 or -Lyt-2 antibody plus C resulted in the complete isolation of L3T4^? Lyt-2⁺ (Lyt-2⁺) or L3T4⁺ Lyt-2^? (L3T4⁺) T cell subset, respectively. This contrasted with the failure of treatment with anti-Lyt-1 antibody plus C to isolate all T cells expressing Lyt-2 marker. It was further demonstrated that each subset of T cells exerted its anti-tumor effect in a tumor-specific way and without a requirement for the other alternative subpopulation of unprimed T cells. These results indicate that Lyt-2⁺ T cell subset can be successfully isolated by treatment with anti-L3T4 but not with anti-Lyt-I antibody plus C, and that each single subset of Lyt-2⁺ and L3T4⁺ T cells can function as in vivo effector T cells.     

CD4 + T Cells from Lymph Nodes Involved by Hodgkin's Disease Showing Response in Autologous Mixed Lymphocyte Reaction, are Polyclonal

Thirteen CD4 + T cell clones (TCCs) showing autologous mixed lymphocyte reaction (AMLR) and 12 CD4 + AMLR-negative TCCs derived from involved lymph nodes (LN) of 4 untreated patients with newly-diagnosed Hodgkin's disease (HD) were analyzed for some functional activities and for T cell receptor (TCR) gamma and beta gene rearrangement

The majority of the AMLR-positive-, but only two AMLR-negative TCCs showed cytolytic potential when assayed by a lectin-dependent assay. In addition, the proportion of clones able to produce interleukin 2 (IL-2) was higher among AMLR-positive- than AMLR-negative TCCs and the amount of IL-2 synthesized by AMLR-positive TCCs was significantly greater than that of AMLR-negative TCCs. In contrast, no difference in the profile of interleukin 4 (IL-4) and interferon-gamma (IFN-γ) production between AMLR-positive- and AMLR-negative TCCs was detected

When AMLR-positive TCCs were analysed for their TCR beta and gamma gene rearrangements, a highly heterogeneous pattern was found. More importantly, TCCs derived from the same donor and displaying the same kind of TCR beta and gamma gene rearrangement showed different patterns of rearrangements, suggesting that CD4 + cells from LN involved by HD, displaying such an unusual functional profile, are polyclonal     

Suppression of Anti-tumor CD4+ T Cell Responsiveness in the Tumor-bearing State and Its Recovery in in vitro Culture Free of Tumor Burden

We investigated whether the responsiveness of anti-tumor CD4⁺ T cells suppressed in the tumor-bearing state is reversed in conditions free of tumor burden. Spleen cells from BALB/c mice bearing a syngeneic tumor (CSA1M) 1–3 wk after inoculation with CSA1M cells produced interleukin-2 (IL-2) and IL-4 upon in vitro culture without addition of exogenous tumor antigens. This lymphokine production was achieved through collaboration between anti-CSA1M CD4⁺ T cells and antigen-presenting cells (APC) that had been pulsed with CSA1M tumor antigens in vivo in the tumor-bearing state. However, spleen cells from late (8–10 wk) tumor-bearing stages produced reduced levels of lymphokine production despite the presence of comparable proportions of CD4⁺ T cells. Because APC in these cell populations exhibited enhanced capacities to present tumor antigens, reduced responsiveness was ascribed to the dysfunction of CD4⁺ T cells themselves. When spleen cells from early tumor-bearing mice were preincubated for 1–2 days and recultured in fresh medium, the magnitude of lymphokine production by these cells was not changed. In contrast, the same protocol of preincubation and reculture for cells from late tumor-bearing mice resulted in the recovery of anti-tumor lymphokine-producing capacity. The recovered capacity was comparable to or slightly higher than that expressed by cells from early tumor-bearing stages. Since the CD4⁺ T cell content did not significantly differ before and after preincubation, enhanced lymphokine production was due to the recovered responsiveness of anti-tumor CD4⁺ helper T cells. The recovery of anti-tumor responsiveness was also induced in vivo by tumor removal at the late tumor-bearing stage: spleen cells from mice 2–4 wk after tumor resection efficiently produced IL-2 and IL-4. These results indicate that the immunodysfunction of anti-tumor CD4⁺ T cells induced in the tumor-bearing state is reversible because release from tumor burden either by preincubation in vitro or by tumor removal in vivo results in almost complete recovery of the potent anti-tumor responsiveness initially expressed.     

CD4+CD25+调节性T细胞与CD4+T、CD8+T细胞在结直肠癌组织中的分布

 目的 分析CD4+CD25+ FOXP3+调节性T细胞（Treg）与CD4+T、CD8+T在结直肠癌（colorectal carcinoma, CRC）组织中的分布及其与临床病理特征之间的关系。方法 收集42例CRC新鲜手术标本,应用冰冻切片、免疫组织化学SP法检测肿瘤组织和癌旁组织中FOXP3+、CD4+T和CD8+T阳性细胞数。结果 CRC患者肿瘤组织中FOXP3表达水平显著升高,与癌旁组织相比差异有统计学意义（P<0.01）;中低分化组Treg细胞数明显高于高分化组（P<0.01）;淋巴结转移组Treg细胞数明显高于无淋巴结转移组（P<0.05）;癌巢内CD4+、CD8+T细胞数及CD4+/CD8+值显著低于间质（P<0.01）;Ⅲ+Ⅳ期、淋巴结转移组癌巢内CD4+/CD8+比值显著低于Ⅰ+Ⅱ期及无淋巴结转移组（P<0.05）;CRC中Treg数量与癌巢内CD4+/CD8+比值显著负相关（r=-0.605, P<0.01）。结论 CRC的发生发展可能与其癌组织局部微环境中Treg数量变化相关,肿瘤局部Treg数量的增多与T淋巴细胞亚群比例失调可能成为肿瘤免疫逃逸的机制之一。     

Reconstitution of Anti-tumor Effects of Lentinan in Nude Mice: Roles of Delayed-type Hypersensitivity Reaction Triggered by CD4-positive T Cell Clone in the Infiltration of Effector Cells into Tumor

Lentinan, an antitumor polysaccharide used clinically in Japan, requires the intact T cell compartment to manifest its antitumor effects. The aim of the current study was to clarify the mechanisms playing crucial roles in the T cell requirement in the expression of antitumor effects of lentinan. Lentinan treatment of BDF1 mice transplanted intradermally with FBL-3 induced complete tumor regression and a marked increase in survival time. The antitumor action of lentinan was abolished in mice treated simultaneously with antibodies to CD4 and CD8 antigens, whereas antibody to CD4, CD8 or NK1.1 alone was ineffective. The natural killer, cytotoxic T lymphocyte, and helper T cell activities were already augmented in this FBL-3/BDF1 system and thus further augmentation of these activities by lentinan was not observed. These activities did not correlate with the antitumor activity of lentinan, as was confirmed in lymphocyte subset depletion experiments. On the contrary, the delayed-type hypersensitivity (DTH) response against tumor-associated antigens was triggered by lentinan and was abrogated only in mice treated simultaneously with antibodies to CD4 and CD8 antigens. Furthermore, a non-cytolytic tumor-associated antigen-specific CD4⁺ T cell clone able to induce the DTH response in concert with lentinan reconstituted the antitumor effects in B6 nude mice when administered with lentinan. These results suggest that, in addition to the augmentation of immune effector cell activity against tumors, infiltration of these cells into the tumor burden initiated by the DTH responses at tumor sites may be involved in eradication of tumors by lentinan.     

肝癌荷瘤小鼠调节性T细胞数量的改变及其与肿瘤生长的关系

目的研究肝癌荷瘤小鼠调节性T细胞数量的改变及其与肿瘤生长的关系。方法采用小鼠肝癌细胞系H22接种BALB／c小鼠,建立肝癌模型;采用流式细胞术方法检测CD4^＋ CD25^＋T／CD4^＋T细胞的比例;以RT-PCR和流式细胞术检测Foxp3基因的表达。以免疫磁珠分选法纯化CD4^＋CD25^＋T和CD4^＋CD25^-T细胞;在体外,用3H-TdR掺入法检测T细胞的增殖情况;在体内,观察荷瘤小鼠来源的CD4^＋CD25^＋T细胞对肿瘤生长的作用。结果（1）荷瘤小鼠在引流淋巴结中,CD4^＋CD25^＋T细胞占CD4＋T细胞（18．80％±0．06％）比例增高,与对照组（9．50％±0．03％）相比,差异有统计学意义（P〈0．01）;在非引流淋巴结（LN）和脾脏（SP）中,荷瘤小鼠CD4^＋CD25^＋T／CD4^＋T比例分别为16．28％±0．02％和17．28％±0．06％,与对照组9．50％±0．03％和11．08％±0．04％相比,差异有统计学意义（P〈0．01,P〈0．05）;同时,调节性T细胞特异性标志Foxp3 mRNA的表达也升高。在同一只荷瘤小鼠中,引流淋巴结中CD4^＋CD25^＋T细胞数量（18．8％±0．06％）较对侧非引流淋巴结（16．28％±0．02％）略有升高,但差异无统计学意义（P〉0．05）。（2）从荷瘤小鼠中纯化的CD4^＋CD25^＋T细胞,在体外对抗CD3单抗的刺激无反应,但能抑制CD4^＋CD25^-T细胞的增殖。（3）CD4^＋CD25^＋T／CD4＋T比例与肿瘤大小呈正相关,并且可以抑制CD4^＋CD25^-T细胞的抗肿瘤效应。结论肝癌细胞在小鼠体内的生长可以提高调节性T细胞的数量,其数量的高低与肿瘤的大小呈正相关,提示清除调节性T细胞将是肿瘤免疫治疗的策略之一。     

结直肠癌患者外周血中CD4+CD45RA+ T和CD4+CD45RO+ T细胞的变化及其意义

目的 探讨外周血中CD4 CD45RA T细胞和CD4 CD45RO T细胞在结直肠癌中的变化及其临床意义。方法 采用流式细胞术检测60例结直肠癌患者手术前、术后1个月和3个月时,外周血的CD4 T细胞、CD4 CD45RA T细胞和CD4 CD45RO T细胞的比例。选取健康查体人群10例作为对照。结果 结直肠癌患者的CD4 T细胞与健康人群相比无差异。CD4 CD45RO T细胞比例明显增高,术后有显著下降,DukesA、B期患者尤其明显;而CD4 CD45RA T细胞比例正好相反。结论 CD4 CD45RA T细胞和CD4 CD45RO T细胞在肿瘤免疫中起重要作用,其表达同结直肠癌的分期和预后有密切关系。     

Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

Cryptotanshinone (CPT), is a quinoid diterpene isolated from the root of the Asian medicinal plant, Salviamiotiorrhiza bunge. Numerous researchers have found that it could work as a potent antitumor agent to inhibittumor growth in vitro, buith there has been much less emphasis on its in vivo role against breast tumors. Usinga mouse tumor model of MCF7 cells, we showed that CPT strongly inhibited MCF7 cell growth in vivo withpolarization of immune reactions toward Th1-type responses, stimulation of naive CD4+ T cell proliferation,and also increased IFN-γ and perforin production of CD4+ T cells in response to tumor-activated splenocytes.Furthermore, data revealed that the cytotoxic activity of CD4+ T cells induced by CPT was markedly abrogatedby concanamycin A(CMA), a perforin inhibitor, but not IFN-γ Ab. On the other hand, after depletion of CD4+T cells or blocked perforin with CMA in a tumor-bearing model, CPT could not effectively suppress tumorgrowth, but this phenomenon could be reversed by injecting naive CD4+ T cells. Thus, our results suggestedthat CPT mainly inhibited breast tumor growth through inducing cytotoxic CD4+ T cells to secrete perforin.We further found that CPT enhanced perforin production of CD4+ T cells by up-regulating JAK2 and STAT4phosphorylation. These findings suggest a novel potential therapeutic role for CPT in tumor therapy, anddemonstrate that CPT performs its antitumor functions through cytotoxic CD4+ T cells.     

监测肾癌患者外周血CD4~+CD25~+调节性T细胞在术后免疫治疗中的作用

目的:探讨肾癌患者外周血CD4+CD25+T淋巴细胞的监测在术后辅助免疫治疗中的作用。方法:将24例肾癌患者随机分为两组:A组,根治性肾切除术后行IFN-α辅助免疫治疗;B组,单纯行根治性肾切除术;C组,10例健康对照。分别在术前、术后1周以及术后3个月免疫治疗结束时采集外周血样本,流式细胞仪检测CD4+、CD8+、CD4+CD25、CD4+CD25high T淋巴细胞亚群含量,并计算各部分比值。结果:A、B组术前CD4+CD25+、CD4+CD25high T淋巴细胞亚群总体上增加,并且其含量随肿瘤分期的进展而增加(P<0.05),但部分患者并不高于健康对照组。免疫治疗后,肾癌患者CD4+CD25+T淋巴细胞总体略有上升,但术前较高的患者中,约2/3下降。结论:利用流式细胞仪监测肾癌患者外周血CD4+CD25+T淋巴细胞亚群可反映机体抗肿瘤免疫状态,有助于预测免疫治疗的预后,为肾癌尤其是早期肾癌术后辅助免疫治疗的选择提供参考。     

Antigen-presenting Cells Constitutively Bind Tumor Antigens in the Tumor-bearing State in vivo to Construct an Effective Immunogenic Unit

Antigen-presenting cells (APC) constitntively process endogenous (self) proteins to bind the processed peptides to la molecules. In the present study, we investigated whether the same associative recognition also holds true for tumor-associated antigens (TAA) that are regarded as "self" molecules in tumor-bearing hosts. The following results were obtained: (i) an APC-depleted splenic T cell population from CSA1M tumor-immunized hosts was stimulated to produce interleukin 2 in vitro when co-cultured with APC from CSA1M-bearing mice, but not from normal mice; and (ii) a Thy-l⁺ cell-depleted APC population from CSA1M-bearing mice could produce CSA1M tumor-specific protection in vivo when inoculated into naive syngeneic mice. These results provide evidence for the functional binding in vivo of TAA to APC in the tumor-bearing state. The results are discussed in the context of the paradox that tumor-bearers fail to reject their own malignancy despite the formation on APC of an effective immunogenic unit which is capable of stimulating tumor-specific T cells.     

食管癌患者外周血调节性T细胞亚群格局变化及其临床意义

[目的]分析食管癌患者外周血CD4+CD25+CD127-调节性T细胞(Treg)占CD4+T细胞的比例变化.[方法]采用流式细胞仪检测104例食管癌患者和68例健康及良性疾病对照者外周血中CD4+CD25+CD127-Treg占CD4+T细胞的比例,分析其与临床分期、淋巴结转移及外膜受侵的关系.[结果]食管癌患者与对照组的外周血CD4+CD25+CD127-Treg占CD4+T细胞比例分别为(5.19％±1.82％)和(4.56％±1.16％),两组比较差异有统计学意义(t=2.544,P=0.012).Ⅱa期CD4+CD25+CD 127-Treg细胞比例分别与Ⅱb期和Ⅲa期比较,差异均有统计学意义(P＜0.01);不同年龄、淋巴结及外膜受侵状况患者的外周血CD4+CD25+CD127-Treg细胞比例变化比较无统计学差异(P＞0.05).[结论]食管癌患者外周血CD4+CD25+CD127-Treg占CD4+T细胞的比例明显升高,且分期高患者升高更为明显,提示可能与食管癌免疫逃逸和免疫耐受有关.     

Cytotoxicity of Histocompatibility Leukocyte Antigen–DR8–restricted CD4+ Killer T Cells against Human Autologous Squamous Cell Carcinoma

Although CD8⁺ killer T cells reacting against human autologous tumor cells have recently been studied in detail, little is known about the cytotoxic mechanism of CD4⁺ T cells against such tumor cells. In order to investigate this, we have established CD4⁺ cytotoxic T lymphocyte TcOSC–20 lines. TcOSC–20 showed selective cytotoxic activity against autologous OSC–20 cells, derived from a cancer of the tongue, in an HLA–DR–restricted fashion. HLA–DR8 (DRB1* 08032) is the only DR molecule expressed on OSC–20 cells, and anti–DRS monoclonal antibody could inhibit the Cytotoxicity, suggesting that HLA–DRB1^★ 08032 is the tumor rejection antigen–presenting moleculeto TcOSC–20. The Fas ligand was expressed on TcOSC–20 lines, and its expression was induced upon mixed lymphocyte–tumor cell culture of autologous peripheral blood lymphocytes. Furthermore, the Cytotoxicity of TcOSC–20 was inhibited by anti–Fas ligand antibody.These data imply that TcOSC–20 lines recognize the tumor antigenic peptide presented by HLA–DR8, and exert Cytotoxicity against autologous tumor cells via a Fas–mediated cytotoxic pathway.