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Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints.

Karachaliou N, Cao MG, Teixidó C, Viteri S, Morales-Espinosa D, Santarpia M, Rosell R - Cancer Biol Med (2015)

Bottom Line: Survival rates for metastatic lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), are poor with 5-year survivals of less than 5%.The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress.However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

View Article: PubMed Central - PubMed

Affiliation: 1 Instituto Oncológico Dr Rosell, Quiron Dexeus University Hospital, Barcelona 08028, Spain ; 2 Pangaea Biotech, Barcelona 08028, Spain ; 3 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina 98122, Italy ; 4 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona 08916, Spain ; 5 Molecular Oncology Research (MORe) Foundation, Barcelona 08028, Spain ; 6 Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti 08916, Spain.

ABSTRACT
Survival rates for metastatic lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), are poor with 5-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-with its capacity for memory, exquisite specificity and central and universal role in human biology-immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

No MeSH data available.


Related in: MedlinePlus

T-cell interaction with APC and tumor cells: the immune checkpoints CTLA-4 and PD-1/PD-L1. Depicted are various ligand-receptor interactions between T-cells, APCs and cancer cells that regulate the T-cell response to antigen. Activation of T-cells is a two-step process that requires recognition of specific peptides presented by MHC on the surface of cancer cells through their TCR, as well as a co-regulatory signal delivered by the CD28 family of receptors (the so-called immune checkpoints). The co-regulatory signal promotes T-cell clonal expansion, cytokine secretion, and functional activity of the T-cell. In the absence of this signal (even in the presence of a target peptide), T-cells fail to respond effectively and are functionally inactivated. This is designed as a fail-safe mechanism to ensure that the immune system is activated at the appropriate time in order to limit collateral damage to normal tissue and minimize the possibility of chronic autoimmune inflammation. Checkpoint pathways regulate these coregulatory signals and can be either stimulatory (switching T-cells on) or inhibitory (switching them off). CTLA-4 and PD-1 deliver inhibitor signals. CTLA-4 negatively regulates T-cell activation by binding to B7 molecules (CD80/86) on the surface of APC or tumor cell. Conversely, when these B7 molecules bind to CD28 they generate the opposite effect, activating signals. When PD-1 binds to either of its ligands (PD-L1 or PD-L2), which are primarily expressed within inflamed tissues and the tumor microenvironment, it results in inhibition of T-cell activity. APC, antigen-presenting cell (dendritic cell, macrophage or any cell that expresses antigen); TCR, T-cell receptor; MHC, major histocompatibility complex.
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f1: T-cell interaction with APC and tumor cells: the immune checkpoints CTLA-4 and PD-1/PD-L1. Depicted are various ligand-receptor interactions between T-cells, APCs and cancer cells that regulate the T-cell response to antigen. Activation of T-cells is a two-step process that requires recognition of specific peptides presented by MHC on the surface of cancer cells through their TCR, as well as a co-regulatory signal delivered by the CD28 family of receptors (the so-called immune checkpoints). The co-regulatory signal promotes T-cell clonal expansion, cytokine secretion, and functional activity of the T-cell. In the absence of this signal (even in the presence of a target peptide), T-cells fail to respond effectively and are functionally inactivated. This is designed as a fail-safe mechanism to ensure that the immune system is activated at the appropriate time in order to limit collateral damage to normal tissue and minimize the possibility of chronic autoimmune inflammation. Checkpoint pathways regulate these coregulatory signals and can be either stimulatory (switching T-cells on) or inhibitory (switching them off). CTLA-4 and PD-1 deliver inhibitor signals. CTLA-4 negatively regulates T-cell activation by binding to B7 molecules (CD80/86) on the surface of APC or tumor cell. Conversely, when these B7 molecules bind to CD28 they generate the opposite effect, activating signals. When PD-1 binds to either of its ligands (PD-L1 or PD-L2), which are primarily expressed within inflamed tissues and the tumor microenvironment, it results in inhibition of T-cell activity. APC, antigen-presenting cell (dendritic cell, macrophage or any cell that expresses antigen); TCR, T-cell receptor; MHC, major histocompatibility complex.

Mentions: One of the key attributes is how the T-cells activate and distinguish “self” from “non-self” molecules. A series of positive and negative costimulatory receptors are expressed on a T-cell at variable levels according to the timing and circumstances of the immune response. The efficiency with which CD4 T-cells direct an immune response demands that proper regulatory measures are in place to prevent immune hyperactivation leading to autoimmune disease. This is very important especially for organs like the lungs that have large mucosal and gas-exchanging surfaces which are constantly exposed to the environment17. Such a critical process involves presentation of antigens to T-cells by antigen presenting cells (APC) and is highly regulated by molecules on T-cells and APC as well as tumor and stromal cells, known as immune checkpoints. Recognition of antigen- major histocompatibility complex (MHC) complexes by the T-cell antigen receptor is not sufficient for activation of naïve T-cells. Additional costimulatory signals are required and are provided by the engagement of CD28 on the T-cell surface with B7 molecules (CD80 and CD86) on the APC18,19 (Figure 1). The role of immune checkpoints is not only to trigger a sufficient immune response but also to inhibit stimulation to ensure the inductive immune response is not excessive. In fact, these immune checkpoints, usually referred to as molecules of inhibitory pathways in the immune system, are crucial for maintaining self-tolerance and modulating physiological immune responses in the periphery, in order to avoid or minimize tissue damage from excess reactions.


Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints.

Karachaliou N, Cao MG, Teixidó C, Viteri S, Morales-Espinosa D, Santarpia M, Rosell R - Cancer Biol Med (2015)

T-cell interaction with APC and tumor cells: the immune checkpoints CTLA-4 and PD-1/PD-L1. Depicted are various ligand-receptor interactions between T-cells, APCs and cancer cells that regulate the T-cell response to antigen. Activation of T-cells is a two-step process that requires recognition of specific peptides presented by MHC on the surface of cancer cells through their TCR, as well as a co-regulatory signal delivered by the CD28 family of receptors (the so-called immune checkpoints). The co-regulatory signal promotes T-cell clonal expansion, cytokine secretion, and functional activity of the T-cell. In the absence of this signal (even in the presence of a target peptide), T-cells fail to respond effectively and are functionally inactivated. This is designed as a fail-safe mechanism to ensure that the immune system is activated at the appropriate time in order to limit collateral damage to normal tissue and minimize the possibility of chronic autoimmune inflammation. Checkpoint pathways regulate these coregulatory signals and can be either stimulatory (switching T-cells on) or inhibitory (switching them off). CTLA-4 and PD-1 deliver inhibitor signals. CTLA-4 negatively regulates T-cell activation by binding to B7 molecules (CD80/86) on the surface of APC or tumor cell. Conversely, when these B7 molecules bind to CD28 they generate the opposite effect, activating signals. When PD-1 binds to either of its ligands (PD-L1 or PD-L2), which are primarily expressed within inflamed tissues and the tumor microenvironment, it results in inhibition of T-cell activity. APC, antigen-presenting cell (dendritic cell, macrophage or any cell that expresses antigen); TCR, T-cell receptor; MHC, major histocompatibility complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493378&req=5

f1: T-cell interaction with APC and tumor cells: the immune checkpoints CTLA-4 and PD-1/PD-L1. Depicted are various ligand-receptor interactions between T-cells, APCs and cancer cells that regulate the T-cell response to antigen. Activation of T-cells is a two-step process that requires recognition of specific peptides presented by MHC on the surface of cancer cells through their TCR, as well as a co-regulatory signal delivered by the CD28 family of receptors (the so-called immune checkpoints). The co-regulatory signal promotes T-cell clonal expansion, cytokine secretion, and functional activity of the T-cell. In the absence of this signal (even in the presence of a target peptide), T-cells fail to respond effectively and are functionally inactivated. This is designed as a fail-safe mechanism to ensure that the immune system is activated at the appropriate time in order to limit collateral damage to normal tissue and minimize the possibility of chronic autoimmune inflammation. Checkpoint pathways regulate these coregulatory signals and can be either stimulatory (switching T-cells on) or inhibitory (switching them off). CTLA-4 and PD-1 deliver inhibitor signals. CTLA-4 negatively regulates T-cell activation by binding to B7 molecules (CD80/86) on the surface of APC or tumor cell. Conversely, when these B7 molecules bind to CD28 they generate the opposite effect, activating signals. When PD-1 binds to either of its ligands (PD-L1 or PD-L2), which are primarily expressed within inflamed tissues and the tumor microenvironment, it results in inhibition of T-cell activity. APC, antigen-presenting cell (dendritic cell, macrophage or any cell that expresses antigen); TCR, T-cell receptor; MHC, major histocompatibility complex.
Mentions: One of the key attributes is how the T-cells activate and distinguish “self” from “non-self” molecules. A series of positive and negative costimulatory receptors are expressed on a T-cell at variable levels according to the timing and circumstances of the immune response. The efficiency with which CD4 T-cells direct an immune response demands that proper regulatory measures are in place to prevent immune hyperactivation leading to autoimmune disease. This is very important especially for organs like the lungs that have large mucosal and gas-exchanging surfaces which are constantly exposed to the environment17. Such a critical process involves presentation of antigens to T-cells by antigen presenting cells (APC) and is highly regulated by molecules on T-cells and APC as well as tumor and stromal cells, known as immune checkpoints. Recognition of antigen- major histocompatibility complex (MHC) complexes by the T-cell antigen receptor is not sufficient for activation of naïve T-cells. Additional costimulatory signals are required and are provided by the engagement of CD28 on the T-cell surface with B7 molecules (CD80 and CD86) on the APC18,19 (Figure 1). The role of immune checkpoints is not only to trigger a sufficient immune response but also to inhibit stimulation to ensure the inductive immune response is not excessive. In fact, these immune checkpoints, usually referred to as molecules of inhibitory pathways in the immune system, are crucial for maintaining self-tolerance and modulating physiological immune responses in the periphery, in order to avoid or minimize tissue damage from excess reactions.

Bottom Line: Survival rates for metastatic lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), are poor with 5-year survivals of less than 5%.The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress.However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

View Article: PubMed Central - PubMed

Affiliation: 1 Instituto Oncológico Dr Rosell, Quiron Dexeus University Hospital, Barcelona 08028, Spain ; 2 Pangaea Biotech, Barcelona 08028, Spain ; 3 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina 98122, Italy ; 4 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona 08916, Spain ; 5 Molecular Oncology Research (MORe) Foundation, Barcelona 08028, Spain ; 6 Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti 08916, Spain.

ABSTRACT
Survival rates for metastatic lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), are poor with 5-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-with its capacity for memory, exquisite specificity and central and universal role in human biology-immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

No MeSH data available.


Related in: MedlinePlus