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Microenvironment of tumor-draining lymph nodes: opportunities for liposome-based targeted therapy.

Chandrasekaran S, King MR - Int J Mol Sci (2014)

Bottom Line: The World Health Organization (WHO) recently reported that the total number of global cancer cases in 2013 reached 14 million, a 10% rise since 2008, while the total number of cancer deaths reached 8.2 million, a 5.2% increase since 2008.Tumor-draining lymph nodes (TDLN), the sentinel nodes, are the first organs of metastasis in several types of cancers.The extent of metastasis in the TDLN is often used in disease staging and prognosis evaluation in cancer patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. sc2389@cornell.edu.

ABSTRACT
The World Health Organization (WHO) recently reported that the total number of global cancer cases in 2013 reached 14 million, a 10% rise since 2008, while the total number of cancer deaths reached 8.2 million, a 5.2% increase since 2008. Metastasis is the major cause of death from cancer, accounting for 90% of all cancer related deaths. Tumor-draining lymph nodes (TDLN), the sentinel nodes, are the first organs of metastasis in several types of cancers. The extent of metastasis in the TDLN is often used in disease staging and prognosis evaluation in cancer patients. Here, we describe the microenvironment of the TDLN and review the recent literature on liposome-based therapies directed to immune cells within the TDLN with the intent to target cancer cells.

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Immune responses in the TDLN: Tumor-associated antigens (TAA) can elicit an anti-tumor immune response in the TDLN through three possible routes: (1) DC in the TDLN ingest TAA transported via passive flow through the lymphatic capillaries to activate naïve T-cells by cross-presentation of antigens; (2) Tumor-infiltrating DC internalize TAA at the primary site and are then transported to the TDLN to activate naïve T-cells; (3) Tumor cells in the TDLN directly present the antigens to naïve T-cells. Once cancer cells reach the TDLN, NK cells are activated that kill tumor cells using effector molecules such as TRAIL and perforins. Activated NK cells secrete immune stimulatory cytokines such as IFN-γ that further activate DC. TAA are presented to naïve T-cells in the TDLN. Antigen presentation on MHC class II molecules activates naïve CD4+ T-cells that differentiate into T-helper (Th) cells. Th2 cells induce cancer cell death via B-cells and Th1 cells directly mediate cancer cell death. Antigen presentation on MHC class I molecules activates naïve CD8+ T-cells that differentiate into cytotoxic T-cells (CTLs) to induce cancer cell death.
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ijms-15-20209-f003: Immune responses in the TDLN: Tumor-associated antigens (TAA) can elicit an anti-tumor immune response in the TDLN through three possible routes: (1) DC in the TDLN ingest TAA transported via passive flow through the lymphatic capillaries to activate naïve T-cells by cross-presentation of antigens; (2) Tumor-infiltrating DC internalize TAA at the primary site and are then transported to the TDLN to activate naïve T-cells; (3) Tumor cells in the TDLN directly present the antigens to naïve T-cells. Once cancer cells reach the TDLN, NK cells are activated that kill tumor cells using effector molecules such as TRAIL and perforins. Activated NK cells secrete immune stimulatory cytokines such as IFN-γ that further activate DC. TAA are presented to naïve T-cells in the TDLN. Antigen presentation on MHC class II molecules activates naïve CD4+ T-cells that differentiate into T-helper (Th) cells. Th2 cells induce cancer cell death via B-cells and Th1 cells directly mediate cancer cell death. Antigen presentation on MHC class I molecules activates naïve CD8+ T-cells that differentiate into cytotoxic T-cells (CTLs) to induce cancer cell death.

Mentions: The immune system has potential for keeping tumor growth under control. The main function of the immune system is to maintain tissue homeostasis by protecting against infectious pathogens/allergens and eliminating damaged cells. Immunologic tolerance prevents an immune response against self-antigens. When tissue homeostasis is chronically perturbed, as in cancer, complex and paradoxical interactions between immune cells and cancer cells can occur that lead to a breakdown of self-tolerance. Leukocytes in and around the developing tumor have been associated with reducing tumor burden [57,58,59]. The adaptive immune response to tumors is directed against tumor-associated antigens (TAA) expressed specifically by tumor cells [60]. The role of TAA-specific T-cell response has been extensively characterized [61]. There is experimental evidence from mouse models of cancer demonstrating the roles of both adaptive and innate immune responses in controlling tumor progression [62,63]. See Ref. [64] for a detailed review on tumor immune surveillance. Tumor progression is a balance between anti-tumor response by the host immune system and immune suppression by tumor cells. Most of the immune surveillance takes place in the TDLN due to its cellular composition and proximity to the primary tumor. TDLN, although very small in size, can have a profound influence on anti-tumor immune response since it is the hub of immune surveillance. Unfortunately, the microenvironment of the TDLN is immune-suppressed in cancer patients, thereby favoring tumor progression and eventually affecting systemic immune response against tumor cells. For a detailed understanding of the molecular basis of immuno-evasion by tumor cells, readers are referred to excellent reviews by Dunn et al. [65,66]. Here we summarize the anti-tumor immune response mediated by different types of cells in the TDLN (Figure 3) and how they are affected by the immunosuppressive microenvironment of the TDLN.


Microenvironment of tumor-draining lymph nodes: opportunities for liposome-based targeted therapy.

Chandrasekaran S, King MR - Int J Mol Sci (2014)

Immune responses in the TDLN: Tumor-associated antigens (TAA) can elicit an anti-tumor immune response in the TDLN through three possible routes: (1) DC in the TDLN ingest TAA transported via passive flow through the lymphatic capillaries to activate naïve T-cells by cross-presentation of antigens; (2) Tumor-infiltrating DC internalize TAA at the primary site and are then transported to the TDLN to activate naïve T-cells; (3) Tumor cells in the TDLN directly present the antigens to naïve T-cells. Once cancer cells reach the TDLN, NK cells are activated that kill tumor cells using effector molecules such as TRAIL and perforins. Activated NK cells secrete immune stimulatory cytokines such as IFN-γ that further activate DC. TAA are presented to naïve T-cells in the TDLN. Antigen presentation on MHC class II molecules activates naïve CD4+ T-cells that differentiate into T-helper (Th) cells. Th2 cells induce cancer cell death via B-cells and Th1 cells directly mediate cancer cell death. Antigen presentation on MHC class I molecules activates naïve CD8+ T-cells that differentiate into cytotoxic T-cells (CTLs) to induce cancer cell death.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264163&req=5

ijms-15-20209-f003: Immune responses in the TDLN: Tumor-associated antigens (TAA) can elicit an anti-tumor immune response in the TDLN through three possible routes: (1) DC in the TDLN ingest TAA transported via passive flow through the lymphatic capillaries to activate naïve T-cells by cross-presentation of antigens; (2) Tumor-infiltrating DC internalize TAA at the primary site and are then transported to the TDLN to activate naïve T-cells; (3) Tumor cells in the TDLN directly present the antigens to naïve T-cells. Once cancer cells reach the TDLN, NK cells are activated that kill tumor cells using effector molecules such as TRAIL and perforins. Activated NK cells secrete immune stimulatory cytokines such as IFN-γ that further activate DC. TAA are presented to naïve T-cells in the TDLN. Antigen presentation on MHC class II molecules activates naïve CD4+ T-cells that differentiate into T-helper (Th) cells. Th2 cells induce cancer cell death via B-cells and Th1 cells directly mediate cancer cell death. Antigen presentation on MHC class I molecules activates naïve CD8+ T-cells that differentiate into cytotoxic T-cells (CTLs) to induce cancer cell death.
Mentions: The immune system has potential for keeping tumor growth under control. The main function of the immune system is to maintain tissue homeostasis by protecting against infectious pathogens/allergens and eliminating damaged cells. Immunologic tolerance prevents an immune response against self-antigens. When tissue homeostasis is chronically perturbed, as in cancer, complex and paradoxical interactions between immune cells and cancer cells can occur that lead to a breakdown of self-tolerance. Leukocytes in and around the developing tumor have been associated with reducing tumor burden [57,58,59]. The adaptive immune response to tumors is directed against tumor-associated antigens (TAA) expressed specifically by tumor cells [60]. The role of TAA-specific T-cell response has been extensively characterized [61]. There is experimental evidence from mouse models of cancer demonstrating the roles of both adaptive and innate immune responses in controlling tumor progression [62,63]. See Ref. [64] for a detailed review on tumor immune surveillance. Tumor progression is a balance between anti-tumor response by the host immune system and immune suppression by tumor cells. Most of the immune surveillance takes place in the TDLN due to its cellular composition and proximity to the primary tumor. TDLN, although very small in size, can have a profound influence on anti-tumor immune response since it is the hub of immune surveillance. Unfortunately, the microenvironment of the TDLN is immune-suppressed in cancer patients, thereby favoring tumor progression and eventually affecting systemic immune response against tumor cells. For a detailed understanding of the molecular basis of immuno-evasion by tumor cells, readers are referred to excellent reviews by Dunn et al. [65,66]. Here we summarize the anti-tumor immune response mediated by different types of cells in the TDLN (Figure 3) and how they are affected by the immunosuppressive microenvironment of the TDLN.

Bottom Line: The World Health Organization (WHO) recently reported that the total number of global cancer cases in 2013 reached 14 million, a 10% rise since 2008, while the total number of cancer deaths reached 8.2 million, a 5.2% increase since 2008.Tumor-draining lymph nodes (TDLN), the sentinel nodes, are the first organs of metastasis in several types of cancers.The extent of metastasis in the TDLN is often used in disease staging and prognosis evaluation in cancer patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. sc2389@cornell.edu.

ABSTRACT
The World Health Organization (WHO) recently reported that the total number of global cancer cases in 2013 reached 14 million, a 10% rise since 2008, while the total number of cancer deaths reached 8.2 million, a 5.2% increase since 2008. Metastasis is the major cause of death from cancer, accounting for 90% of all cancer related deaths. Tumor-draining lymph nodes (TDLN), the sentinel nodes, are the first organs of metastasis in several types of cancers. The extent of metastasis in the TDLN is often used in disease staging and prognosis evaluation in cancer patients. Here, we describe the microenvironment of the TDLN and review the recent literature on liposome-based therapies directed to immune cells within the TDLN with the intent to target cancer cells.

Show MeSH
Related in: MedlinePlus