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Immune cell recruitment and cell-based system for cancer therapy.

Gao JQ, Okada N, Mayumi T, Nakagawa S - Pharm. Res. (2007)

Bottom Line: Immune cells, such as cytotoxic T lymphocytes, natural killer cells, B cells, and dendritic cells, have a central role in cancer immunotherapy.It is well established that the basis and premise of immunotherapy is the accumulation of effective immune cells in tumor tissues.Recent characterization of various chemokines and chemokine receptors in the immune system has increased our knowledge of the regulatory mechanisms of the immune response and tolerance based on immune cell localization.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmaceutical Sciences, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, People's Republic of China. gaojianqing1029@yahoo.com.cn

ABSTRACT
Immune cells, such as cytotoxic T lymphocytes, natural killer cells, B cells, and dendritic cells, have a central role in cancer immunotherapy. Conventional studies of cancer immunotherapy have focused mainly on the search for an efficient means to prime/activate tumor-associated antigen-specific immunity. A systematic understanding of the molecular basis of the trafficking and biodistribution of immune cells, however, is important for the development of more efficacious cancer immunotherapies. It is well established that the basis and premise of immunotherapy is the accumulation of effective immune cells in tumor tissues. Therefore, it is crucial to control the distribution of immune cells to optimize cancer immunotherapy. Recent characterization of various chemokines and chemokine receptors in the immune system has increased our knowledge of the regulatory mechanisms of the immune response and tolerance based on immune cell localization. Here, we review the immune cell recruitment and cell-based systems that can potentially control the systemic pharmacokinetics of immune cells and, in particular, focus on cell migrating molecules, i.e., chemokines, and their receptors, and their use in cancer immunotherapy.

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Related in: MedlinePlus

Enhancement of DC migration to lymphoid tissues by chemokine receptor expression on DCs. Increasing the migratory ability of a DC vaccine toward lymphoid tissue would remarkably improve the efficacy of DC-based immunotherapy. The chemokine receptor (CCR7) facilitates DC migration to lymphoid tissues. Superior lymphoid tissue-accumulation of DCs transduced with the CCR7 gene (CCR7/DCs) is advantageous as a vaccine carrier because it efficiently activates immune effector cells in regional lymph nodes.
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Fig3: Enhancement of DC migration to lymphoid tissues by chemokine receptor expression on DCs. Increasing the migratory ability of a DC vaccine toward lymphoid tissue would remarkably improve the efficacy of DC-based immunotherapy. The chemokine receptor (CCR7) facilitates DC migration to lymphoid tissues. Superior lymphoid tissue-accumulation of DCs transduced with the CCR7 gene (CCR7/DCs) is advantageous as a vaccine carrier because it efficiently activates immune effector cells in regional lymph nodes.

Mentions: Efficient CCR7-gene transduction to DCs is proposed as a preparatory method for this novel “lymphoid tissue-directivity DC” vaccine (Fig. 3). CCR7/DCs, which are DCs transfected by CCR7-encoding Ad-RGD, acquire strong chemotactic activity for CCL21 and exhibit an immunophenotype similar to mature, but not immature, DCs with regard to MHC/costimulatory molecule-expression levels and allogenic T cell proliferation-stimulating ability, while maintaining inherent endocytotic activity (147). Importantly, CCR7/DCs injected intradermally into mice accumulate in draining lymph nodes approximately 5.5-fold more efficiently than control Ad-RGD-transduced DCs. Reflecting these properties of CCR7/DCs, DC vaccines genetically engineered to simultaneously express endogenous antigen and CCR7 could elicit a more effective antigen-specific immune response in vivo using a lower dose than DC vaccine transduced with antigen alone. Therefore, the application of CCR7/DCs having positive migratory ability to lymphoid tissues might contribute to reduce the effort and cost associated with DC vaccine preparation by considerably reducing the DC vaccine dose needed to achieve effective treatment by DC-based immunotherapy. In another report, Yang et al. used a different strategy: they transduced DCs with an adenovirus vector expressing secondary lymphoid chemokine (CCL21) and evaluated its antitumor activity in a murine model of spontaneous bronchoalveolar cell carcinoma (148). The transgenic mice (CC-10 TAg) expressed the SV40 large T antigen (TAg) under the Clara cell promoter, developed bilateral, multifocal, and pulmonary adenocarcinomas, and died at 4 months of age as a result of progressive pulmonary tumor burden. A single intratracheal administration of CCL21 gene-modified DCs (DC-AdCCL21) markedly reduced the tumor burden with extensive mononuclear cell infiltration of the tumors. The reduced tumor burden was accompanied by the enhanced production of type 1 cytokines such as interferon-gamma, IL-12, and GM-CSF and antiangiogenic chemokines such as CXCL9 and CXCL10. At the same time, there was a concomitant decrease in the immunosuppressive molecules IL-10, transforming growth factor-beta, and prostaglandin E(2) in the tumor microenvironment. The DC-AdCCL21 treatment group had a significantly greater percentage of tumor-specific T cells releasing interferon-gamma compared with the controls. Continuous therapy with weekly intranasal delivery of DC-AdCCL21 significantly prolonged median survival time in the CC-10 TAg mice. Both innate NK and specific T cell antitumor responses significantly increased following DC-AdCCL21 therapy. These results provide a strong rationale for further evaluation of intrapulmonary-administered DC-AdCCL21 to regulate tumor immunity and genetic immunotherapy for lung cancer.Fig. 3


Immune cell recruitment and cell-based system for cancer therapy.

Gao JQ, Okada N, Mayumi T, Nakagawa S - Pharm. Res. (2007)

Enhancement of DC migration to lymphoid tissues by chemokine receptor expression on DCs. Increasing the migratory ability of a DC vaccine toward lymphoid tissue would remarkably improve the efficacy of DC-based immunotherapy. The chemokine receptor (CCR7) facilitates DC migration to lymphoid tissues. Superior lymphoid tissue-accumulation of DCs transduced with the CCR7 gene (CCR7/DCs) is advantageous as a vaccine carrier because it efficiently activates immune effector cells in regional lymph nodes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2279154&req=5

Fig3: Enhancement of DC migration to lymphoid tissues by chemokine receptor expression on DCs. Increasing the migratory ability of a DC vaccine toward lymphoid tissue would remarkably improve the efficacy of DC-based immunotherapy. The chemokine receptor (CCR7) facilitates DC migration to lymphoid tissues. Superior lymphoid tissue-accumulation of DCs transduced with the CCR7 gene (CCR7/DCs) is advantageous as a vaccine carrier because it efficiently activates immune effector cells in regional lymph nodes.
Mentions: Efficient CCR7-gene transduction to DCs is proposed as a preparatory method for this novel “lymphoid tissue-directivity DC” vaccine (Fig. 3). CCR7/DCs, which are DCs transfected by CCR7-encoding Ad-RGD, acquire strong chemotactic activity for CCL21 and exhibit an immunophenotype similar to mature, but not immature, DCs with regard to MHC/costimulatory molecule-expression levels and allogenic T cell proliferation-stimulating ability, while maintaining inherent endocytotic activity (147). Importantly, CCR7/DCs injected intradermally into mice accumulate in draining lymph nodes approximately 5.5-fold more efficiently than control Ad-RGD-transduced DCs. Reflecting these properties of CCR7/DCs, DC vaccines genetically engineered to simultaneously express endogenous antigen and CCR7 could elicit a more effective antigen-specific immune response in vivo using a lower dose than DC vaccine transduced with antigen alone. Therefore, the application of CCR7/DCs having positive migratory ability to lymphoid tissues might contribute to reduce the effort and cost associated with DC vaccine preparation by considerably reducing the DC vaccine dose needed to achieve effective treatment by DC-based immunotherapy. In another report, Yang et al. used a different strategy: they transduced DCs with an adenovirus vector expressing secondary lymphoid chemokine (CCL21) and evaluated its antitumor activity in a murine model of spontaneous bronchoalveolar cell carcinoma (148). The transgenic mice (CC-10 TAg) expressed the SV40 large T antigen (TAg) under the Clara cell promoter, developed bilateral, multifocal, and pulmonary adenocarcinomas, and died at 4 months of age as a result of progressive pulmonary tumor burden. A single intratracheal administration of CCL21 gene-modified DCs (DC-AdCCL21) markedly reduced the tumor burden with extensive mononuclear cell infiltration of the tumors. The reduced tumor burden was accompanied by the enhanced production of type 1 cytokines such as interferon-gamma, IL-12, and GM-CSF and antiangiogenic chemokines such as CXCL9 and CXCL10. At the same time, there was a concomitant decrease in the immunosuppressive molecules IL-10, transforming growth factor-beta, and prostaglandin E(2) in the tumor microenvironment. The DC-AdCCL21 treatment group had a significantly greater percentage of tumor-specific T cells releasing interferon-gamma compared with the controls. Continuous therapy with weekly intranasal delivery of DC-AdCCL21 significantly prolonged median survival time in the CC-10 TAg mice. Both innate NK and specific T cell antitumor responses significantly increased following DC-AdCCL21 therapy. These results provide a strong rationale for further evaluation of intrapulmonary-administered DC-AdCCL21 to regulate tumor immunity and genetic immunotherapy for lung cancer.Fig. 3

Bottom Line: Immune cells, such as cytotoxic T lymphocytes, natural killer cells, B cells, and dendritic cells, have a central role in cancer immunotherapy.It is well established that the basis and premise of immunotherapy is the accumulation of effective immune cells in tumor tissues.Recent characterization of various chemokines and chemokine receptors in the immune system has increased our knowledge of the regulatory mechanisms of the immune response and tolerance based on immune cell localization.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmaceutical Sciences, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, People's Republic of China. gaojianqing1029@yahoo.com.cn

ABSTRACT
Immune cells, such as cytotoxic T lymphocytes, natural killer cells, B cells, and dendritic cells, have a central role in cancer immunotherapy. Conventional studies of cancer immunotherapy have focused mainly on the search for an efficient means to prime/activate tumor-associated antigen-specific immunity. A systematic understanding of the molecular basis of the trafficking and biodistribution of immune cells, however, is important for the development of more efficacious cancer immunotherapies. It is well established that the basis and premise of immunotherapy is the accumulation of effective immune cells in tumor tissues. Therefore, it is crucial to control the distribution of immune cells to optimize cancer immunotherapy. Recent characterization of various chemokines and chemokine receptors in the immune system has increased our knowledge of the regulatory mechanisms of the immune response and tolerance based on immune cell localization. Here, we review the immune cell recruitment and cell-based systems that can potentially control the systemic pharmacokinetics of immune cells and, in particular, focus on cell migrating molecules, i.e., chemokines, and their receptors, and their use in cancer immunotherapy.

Show MeSH
Related in: MedlinePlus