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encore19850铜虫 (小有名气)
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[求助]
求助段落中心意思，急急急。大谢。不需要逐字逐句~
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CO-SIGNALING MOLECULES AND ANTITUMOR IMMUNITY IN AGING Co-signaling signals are essential for the augmentation of APC-mediated T cell responses in antitumor immunity. For example, expression of CD80 (B7.1) and CD86 (B7.2) on APCs or tumor cells is crucial for promoting antitumor T cell responses.82 Several studies have demonstrated decreased expression of these co-signaling molecules on aged DCs, which may contribute to the reduced capacity for T cell stimulation by DCs during aging.73,74 Lustgarten et al. investigated whether CD80 expression on tumor cells was important for the enhancement of antitumor responses in aged mice. Immunization with the foreign protein enhanced GFP (EGFP)-expressing BM-185 pre-B-cell lymphoma cells (BM-185-EGFP) yielded an antitumor immune response in young, but not in aged, mice. However, immunization with CD80-expressing BM-185-EGFP tumor cells (BM-185-EGFP-CD80) yielded an antitumor immune response in both young and aged mice, although the tumor rejection was lower in aged mice compared with young mice.83 There is increasing evidence that several other members of the TNFR family, including OX40 (CD134), 4-1BB (CD137), CD27, and CD30, may be important as secondary costimulatory molecules when co-signaling molecules are reduced and insufficient for T cell stimulation during aging. In studies evaluating the effect of additional OX40 signaling in antitumor immune responses in aged mice, immunization with BM-185-EGFP-CD80 in combination with an anti-OX40 mAb markedly improved antitumor response in aged mice.83 Similarly, an apoptotic tumor cell-pulsed DC vaccine in combination with an anti- OX40 mAb significantly enhanced the antitumor immune response in aged mice.84 Interestingly, Ruby and Weinberg investigated the efficacy of an anti-OX40 mAb alone in middle-aged and elderly sarcoma-tumor-bearing mice, and confirmed that the administration of the mAb to these mice significantly reduced antitumor efficacy because of the decreased number of differentiated T cells, and was not due to an alteration of the surface expression of OX40 on T cells.85,86 Furthermore, administration of the anti-OX40 mAb in combination with IL-12, a cytokine that is essential for T cell differentiation, partially restored the deficiency in OX40-mediated antitumor efficacy in older mice. 4-1BB is also a member of the TNFR family that is expressed on activated T cells and co-stimulates both CD4 and CD8 T cells. In particular, Bansal- Pakala and Croft reported that the administration of an agonist Ab to 4-1BB rescued defective T cell priming in aged mice.87 Similarly, Sharma et al. revealed that apoptotic tumor cell-pulsed DC vaccination in combination with an anti-4-1BB mAb significantly enhanced the antitumor immune response in aged mice.84 These results suggest that the insufficient antitumor immune responses in aging may be restored by the efficient expression of co-stimulatory signals. V. TLRS AND ANTITUMOR IMMUNITY IN AGING Recent studies have revealed that innate immune responses and adaptive immune responses collaborate to induce a strong antitumor immune response. For example, the mediation of innate immune responses by members of the Toll-like receptor (TLR) family results in the subsequent induction of protective adaptive immune responses in antitumor immunity.88,89 Several studies have demonstrated that advancing age may affect the expression and function of TLRs, and the response to TLR ligands in the innate immune system. Renshaw et al. reported that aged splenic and peritoneal macrophages express significantly lower levels of TLRs and secrete significantly lower levels of cytokines after stimulation with various TLR ligands.90 Previous studies have shown that CpG-ODN stimulates plasmacytoid DCs to produce type I interferons (IFN α and β), which inhibit the synthesis of Th2 cytokines by CD4 T cells and induce IL-4-inhibited Th1 cells to synthesize IL-2, IL-12, and IFN-γ. In turn, these induce NK cells, NKT cells, and CTLs in the antitumor immune responses.91 Sharma et al. reported that the intratumoral injection of CpG-ODN yielded complete rejection of in vivo tumors in both young and old mice; however, injection of poly I:C exhibited in vivo tumor rejection only in young mice.92 The authors also revealed that the induction of the antitumor immune response by in vivo challenge with CpG-ODN, but not poly I:C in old mice, was correlated with the upregulation of pro-inflammatory cytokine secretion, significant accumulation of CD4 T cells, CD8 T cells, NK cells, and APCs within the tumor, and reduction of the number of Tregs within the tumor. These results indicate that the efficacy of TLR ligands in antitumor immunity may be reduced during the aging process. Moreover, there is a difference in capacity to induce immune responses among the various TLR ligands in the old mice.92 It appears that CpG-ODN may constitute a possible therapeutic approach to overcome the age-associated immune defects in cancer immunotherapy and restore the antitumor immune response in the elderly. VI. IMMUNOSUPPRESSIVE CELLS AND ANTITUMOR IMMUNITY IN AGING Advancing age may alter the prevalence and function of immune suppressive cells such as CD4+ CD25+FoxP3+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Tregs accumulate in tumor-bearing hosts and play fundamental roles in blocking antitumor immune responses.93,94 MDSCs, a heterogeneous population comprised of immature myeloid cells, accumulate within sites of cancer, inflammation, and infection,95,96 and have a strong capability to suppress both adaptive and innate immune responses. Accumulating evidence has revealed that the elimination of either population in a tumorbearing host may contribute to enhanced antitumor immune responses. Whereas the age-dependent changes in the number of Tregs and their function remain controversial, 30 several studies have suggested that Tregs accumulate with age and are involved in the age-associated immune dysfunction. Gregg et al. reported that the number of human peripheral blood Tregs increases with age, whereas the function of these cells is comparable between the young and the old.97 Sharma et al. reported that the increased frequency of Tregs in aged mice prevented the cytotoxic T cell response in aged tumorbearing mice.98 Pan et al. also showed that the accumulation of Tregs in aged humans and mice was closely associated with lung tumor burden.99 Further studies will be required to test Treg frequency and functions in the periphery versus within the tumor itself, and the impact on clinical outcome. Similar to the Tregs, it has been demonstrated that the decline of antitumor T cell function in aged animal is also correlated with the accumulation of MDSCs with age. Grizzle et al. revealed that MDSCs are increased in the spleen of aged mice, and that adoptive transfer of these aged MDSCs delayed tumor rejection significantly in young tumor-bearing mice Similarly, Sharma et al. revealed that apoptotic tumor cell-pulsed DC vaccination in combination with an anti-4-1BB mAb significantly enhanced the antitumor immune response in aged mice.84 These results suggest that the insufficient antitumor immune responses in aging may be restored by the efficient expression of co-stimulatory signals. Tomihara et al. Page 5 Crit Rev Oncog. Author manuscript; available in PMC 2014 March 20. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript V. TLRS AND ANTITUMOR IMMUNITY IN AGING Recent studies have revealed that innate immune responses and adaptive immune responses collaborate to induce a strong antitumor immune response. For example, the mediation of innate immune responses by members of the Toll-like receptor (TLR) family results in the subsequent induction of protective adaptive immune responses in antitumor immunity.88,89 Several studies have demonstrated that advancing age may affect the expression and function of TLRs, and the response to TLR ligands in the innate immune system. Renshaw et al. reported that aged splenic and peritoneal macrophages express significantly lower levels of TLRs and secrete significantly lower levels of cytokines after stimulation with various TLR ligands.90 Previous studies have shown that CpG-ODN stimulates plasmacytoid DCs to produce type I interferons (IFN α and β), which inhibit the synthesis of Th2 cytokines by CD4 T cells and induce IL-4-inhibited Th1 cells to synthesize IL-2, IL-12, and IFN-γ. In turn, these induce NK cells, NKT cells, and CTLs in the antitumor immune responses.91 Sharma et al. reported that the intratumoral injection of CpG-ODN yielded complete rejection of in vivo tumors in both young and old mice; however, injection of poly I:C exhibited in vivo tumor rejection only in young mice.92 The authors also revealed that the induction of the antitumor immune response by in vivo challenge with CpG-ODN, but not poly I:C in old mice, was correlated with the upregulation of pro-inflammatory cytokine secretion, significant accumulation of CD4 T cells, CD8 T cells, NK cells, and APCs within the tumor, and reduction of the number of Tregs within the tumor. These results indicate that the efficacy of TLR ligands in antitumor immunity may be reduced during the aging process. Moreover, there is a difference in capacity to induce immune responses among the various TLR ligands in the old mice.92 It appears that CpG-ODN may constitute a possible therapeutic approach to overcome the age-associated immune defects in cancer immunotherapy and restore the antitumor immune response in the elderly. VI. IMMUNOSUPPRESSIVE CELLS AND ANTITUMOR IMMUNITY IN AGING Advancing age may alter the prevalence and function of immune suppressive cells such as CD4+ CD25+FoxP3+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Tregs accumulate in tumor-bearing hosts and play fundamental roles in blocking antitumor immune responses.93,94 MDSCs, a heterogeneous population comprised of immature myeloid cells, accumulate within sites of cancer, inflammation, and infection,95,96 and have a strong capability to suppress both adaptive and innate immune responses. Accumulating evidence has revealed that the elimination of either population in a tumorbearing host may contribute to enhanced antitumor immune responses. Whereas the age-dependent changes in the number of Tregs and their function remain controversial, 30 several studies have suggested that Tregs accumulate with age and are involved in the age-associated immune dysfunction. Gregg et al. reported that the number of human peripheral blood Tregs increases with age, whereas the function of these cells is comparable between the young and the old.97 Sharma et al. reported that the increased frequency of Tregs in aged mice prevented the cytotoxic T cell response in aged tumorbearing mice.98 Pan et al. also showed that the accumulation of Tregs in aged humans and mice was closely associated with lung tumor burden.99 Further studies will be required to test Treg frequency and functions in the periphery versus within the tumor itself, and the impact on clinical outcome. Similar to the Tregs, it has been demonstrated that the decline of antitumor T cell function in aged animal is also correlated with the accumulation of MDSCs with age. Grizzle et al. revealed that MDSCs are increased in the spleen of aged mice, and that adoptive transfer of these aged MDSCs delayed tumor rejection significantly in young tumor-bearing mice.100 Tomihara et al. Page 6 Crit Rev Oncog. Author manuscript; available in PMC 2014 March 20. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript More recently, the proportion of MDSCs was found to be elevated significantly in elderly patients with a history of cancer.101 Importantly, a number of pro-inflammatory cytokines that are required for the differentiation of MDSCs (e.g., TNF-α, IL-6, and IL-1β) are increased in the old,101,102 suggesting that the age-related inflammatory milieu possibly promotes the accumulation and activation of MDSCs that subsequently could contribute to the increased aging-associated cancer incidence. Interestingly, it is possible to note a mutual interaction between the Treg cells and the MDSCs. In fact, MDSC contributes to Treg induction in cancer, but, in turn, Tregs may regulate MDSC expansion with a mechanism of positive feedback. In support, our group reported an age-specific inverse correlation between the prevalence of Tregs and MDSCs.103 We examined the antitumor response to Treg depletion in the B16 melanoma model and revealed that Treg depletion alone using denileukin diftitox (DT) exerted therapeutic effects only in young mice but not aged mice. Furthermore, Treg depletion using DT in aged mice resulted in an increased number of MDSCs. MDSC depletion in combination with Treg depletion restored the impaired efficacy of Treg depletion in aged mice, suggesting that Tregs control the prevalence of MDSCs in aged mice and that Treg depletion in combination with MDSC depletion may be an effective cancer immune therapy approach for the elderly. |
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weichao123
金虫 (小有名气)
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encore19850(RXMCDM代发): 金币+10, 多谢应助！ 2015-02-01 08:53:54
encore19850(RXMCDM代发): 金币+10, 多谢应助！ 2015-02-01 08:53:54
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CO-信号分子和抗肿瘤免疫中的老化 共信令信号是用于APC介导的T细胞应答的增强必不可少 抗肿瘤免疫。例如， CD80 （ B7.1 ）及CD86 （ B7.2 ）对装甲运兵车的表达或 肿瘤细胞是用于促进抗肿瘤T细胞responses.82几项研究有关键 表现在减少老年的DC ，这些共同信号分子的表达，这 在aging.73,74可能有助于T细胞刺激树突状能力下降 勒斯特加滕等。调查了在肿瘤细胞上的CD80表达是否是重要的 增强老年小鼠的抗肿瘤反应。接种外源蛋白 增强的GFP （绿色荧光蛋白） -expressing BM- 185的前B细胞淋巴瘤细胞（BM -185 -EGFP ） 产生在年轻的抗肿瘤免疫反应，但不是在老年小鼠。然而， 免疫CD80表达的BM- 185 -EGFP肿瘤细胞（BM -185 -EGFP- CD80 ） 在取得了年轻和老年小鼠的抗肿瘤免疫反应，虽然肿瘤 抑制明显低于老年小鼠与年轻mice.83比较 有越来越多的证据表明，肿瘤坏死因子受体家族的其他几个成员，包括 OX40 （ CD134 ） ， 4-1BB （ CD137 ） ， CD27 ，和CD30，可能是重要的，因为辅助共刺激 分子时共信号分子被减少和不足的T细胞 老化过程中的刺激。在研究评估更多的OX40信号的影响 在老年小鼠的抗肿瘤免疫应答，免疫BM- 185 -EGFP- CD80在 与老年抗OX40单抗显着改善的抗肿瘤反应的组合 mice.83类似地，在组合的凋亡肿瘤细胞致敏的DC疫苗与抗 OX40单抗显著提高老年mice.84的抗肿瘤免疫反应 有趣的是， Ruby和温伯格调查的抗OX40单抗的疗效独 中年和老年肉瘤荷瘤小鼠，并证实该管理 单克隆抗体对这些小鼠显著减少由于减少抗肿瘤功效 号分化T细胞的，并且不是由于表面表达的改变 OX40对T cells.85,86此外，抗OX40单抗的施用组合 与IL- 12，细胞因子，是用于T细胞分化所必需的，部分还原的 不足OX40介导的抗肿瘤效果在老年小鼠。 4-1BB也是一个构件 被表达在活化的T细胞和共能刺激CD4和CD8的TNFR家族 T细胞。特别是， Bansal- Pakala和克罗夫特报道，激动剂的给药 AB公司4-1BB救出缺陷的T细胞引发老年mice.87 同样， Sharma等。发现在细胞凋亡的肿瘤细胞致敏的DC疫苗接种 用抗4-1BB组合MAB显著增强了抗肿瘤免疫 响应老年mice.84这些结果表明，在不充分的抗肿瘤免疫 在老化的反应可通过共刺激信号的有效表达恢复。 五， TLRS和抗肿瘤免疫中的老化 最近的研究表明，先天免疫应答和适应性免疫反应 协作，以诱导强的抗肿瘤免疫应答。例如，中介 由Toll样受体的成员（TLR）家族导致先天免疫反应 随后诱导抗肿瘤immunity.88,89保护性免疫反应 几项研究已经表明，年龄增长可能会影响表达和 功能的TLR的，并且在先天免疫系统对TLR配体的应答。伦肖 等。报道称，中年脾及腹腔巨噬细胞表达显著降低 TLR的水平，以及刺激后分泌的细胞因子的显著较低水平 不同的TLR ligands.90以往的研究表明，的CpG -ODN可以刺激 浆的DCs产生的I型干扰素（干扰素α和β ），其抑制的合成 通过CD4T细胞Th2细胞因子并诱导IL-4抑制Th1细胞合成IL-2， IL-12， 和IFN-γ 。反过来，这些诱导NK细胞， NKT细胞，和的CTL在抗肿瘤免疫 responses.91 Sharma等。报道称，瘤内注射的CpG -ODN墓内 在体内肿瘤的年轻和年老小鼠完全拒绝;然而，注射聚 I：C展出体内肿瘤排斥只有在年轻的mice.92作者还透露， 诱导通过体内挑战与CpG的寡核苷酸的抗肿瘤免疫应答的，但 不聚I：C在老年小鼠，率与促炎症细胞因子的表达上调 分泌， CD4 + T细胞的显著积累， CD8 + T细胞内，NK细胞，和的APC 肿瘤，和减少的Treg的肿瘤内的数目。这些结果表明 TLR的配体功效的抗肿瘤免疫的老化过程中可减少 流程。此外，有在容量的差，以诱发其中的免疫应答 各种TLR配体的老mice.92似乎的CpG -ODN可构成一个可能的 治疗方法，以克服在癌症中的年龄相关的免疫缺陷 免疫治疗和恢复中老年人的抗肿瘤免疫反应。 VI 。免疫抑制细胞和抗肿瘤免疫中的老化 年龄的增长可能会改变免疫抑制细胞如患病率和功能 CD4 + CD25 + Foxp3 +调节性T细胞（ Treg细胞）和骨髓源性抑制细胞 （肌源性干细胞） 。调节性T细胞积聚在肿瘤携带主机和发挥基本作用在阻断 抗肿瘤免疫responses.93,94的MDSCs ，异质群体包括 未成熟髓样细胞，积聚的癌症，炎症和感染， 95,96位点内 并且有很强的能力，同时抑制适应性和先天免疫反应。 越来越多的证据显示，消除任何人口中荷瘤 主机可能有助于增强抗肿瘤免疫应答。 而在调节性T细胞的数目的年龄依赖性的变化和它们的功能保持 有争议的， 30几个研究已经表明，调节性T细胞积累与年龄，是 参与年龄相关的免疫功能紊乱。格雷格等。报道称，数 人外周血Treg细胞随着年龄的增加，而这些细胞的功能是 可比的年轻人和old.97夏尔马等人之间。报告说，增加的 调节性T细胞在老年小鼠的频率防止老年荷瘤的细胞毒性T细胞反应 mice.98 Pan等。还表明，调节性T细胞的老年人的积累和 小鼠紧密burden.99进一步的研究将要求肺肿瘤相关 测试的Treg频率和功能，在周边部与肿瘤本身内，并且 对临床结果的影响。 类似的Treg ，它已被证明的抗肿瘤T细胞功能中的下降 老年动物也与肌源性干细胞随着年龄的积累。灰色等。 透露，肌源性干细胞在老年小鼠的脾增大，而继转让 这些年龄肌源性干细胞延缓肿瘤抑制显著年轻荷瘤mice.100 Tomihara等。第6页 暴击牧师Oncog 。作者的手稿;可在2014年PMC 3月20日。 NIH -PA作者手稿NIH -PA作者手稿NIH -PA作者手稿 最近，肌源性干细胞的比例被认为是老年显著升高 患者cancer.101史 重要的是，许多促炎细胞因子的所需要的分化 肌源性干细胞（例如， TNF-α， IL-6和IL-1β ） ，在旧的增加， 101102提示 年龄相关的炎症环境可能促进的积累和活化 肌源性干细胞在此之后可有助于增加衰老相关癌症 发病率。有趣的是，有可能要注意的Treg细胞和之间的相互作用 该肌源性干细胞。事实上， MDSC有助于Treg细胞的诱导在癌症，但反过来，调节性T细胞可 规范MDSC扩张与正反馈的机制。在支持，我们的团队 报道调节性T细胞和MDSCs.103的患病率之间的特定年龄呈负相关 我们审查了黑色素瘤模型中的抗肿瘤反应调节性T细胞耗竭和 透露，调节性T细胞耗竭单独使用尼白介素（ DT ）发挥治疗作用 只有在年轻的小鼠，但不是老年小鼠。此外，在老年小鼠使用DT调节性T细胞耗竭 导致的MDSCs的数量增加。 MDSC枯竭与调节性T细胞结合 枯竭恢复Treg细胞耗竭的疗效受损老年小鼠，这表明 调节性T细胞控制肌源性干细胞的患病率在老年小鼠和调节性T细胞耗竭组合 同的MDSC枯竭可能是老年人的有效的癌症免疫治疗的方法。 |
2楼2014-12-31 15:21:57