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Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators.

Le Mercier I, Lines JL, Noelle RJ - Front Immunol (2015)

Bottom Line: Releasing these brakes has emerged as an exciting strategy for cancer treatment.Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation.In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH , USA.

ABSTRACT
In the last two years, clinical trials with blocking antibodies to the negative checkpoint regulators CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. Multiple negative checkpoint regulators protect the host against autoimmune reactions but also restrict the ability of T cells to effectively attack tumors. Releasing these brakes has emerged as an exciting strategy for cancer treatment. Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation. In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses. In this review, we describe the current knowledge on the recently discovered negative checkpoint regulators, future targets for immunotherapy.

No MeSH data available.


Related in: MedlinePlus

Summary of NCRs expression on immune cell populations and their functions.
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Figure 1: Summary of NCRs expression on immune cell populations and their functions.

Mentions: As summarized in Figure 1, these new NCR pathways present striking similarities. Most NCRs are induced upon T cell activation and terminate or constrain the effector response by feedback inhibition. Some are also expressed on the APCs and regulate their stimulatory function. Conversely, multiple NCRs are expressed on Tregs and Tr1 and promote their differentiation and/or suppressive function. Most are also upregulated on dysfunctional T cells in chronic viral infections and cancer. Finally, most have multiple binding partners with which interactions are bidirectional with regard to signaling, rendering the assignment of ligand and receptor ambiguous or irrelevant. However, despite those similarities, their functions are mostly non-redundant. Therefore, blocking several of these pathways synergize in restoring efficient anti-tumor responses in preclinical models. The recently found astounding efficacy of combined anti-CTLA-4 and anti-PD-1 therapy in advanced melanoma patients argues in favor of targeting multiple pathways for future immunotherapeutic approaches (167–169).


Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators.

Le Mercier I, Lines JL, Noelle RJ - Front Immunol (2015)

Summary of NCRs expression on immune cell populations and their functions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544156&req=5

Figure 1: Summary of NCRs expression on immune cell populations and their functions.
Mentions: As summarized in Figure 1, these new NCR pathways present striking similarities. Most NCRs are induced upon T cell activation and terminate or constrain the effector response by feedback inhibition. Some are also expressed on the APCs and regulate their stimulatory function. Conversely, multiple NCRs are expressed on Tregs and Tr1 and promote their differentiation and/or suppressive function. Most are also upregulated on dysfunctional T cells in chronic viral infections and cancer. Finally, most have multiple binding partners with which interactions are bidirectional with regard to signaling, rendering the assignment of ligand and receptor ambiguous or irrelevant. However, despite those similarities, their functions are mostly non-redundant. Therefore, blocking several of these pathways synergize in restoring efficient anti-tumor responses in preclinical models. The recently found astounding efficacy of combined anti-CTLA-4 and anti-PD-1 therapy in advanced melanoma patients argues in favor of targeting multiple pathways for future immunotherapeutic approaches (167–169).

Bottom Line: Releasing these brakes has emerged as an exciting strategy for cancer treatment.Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation.In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH , USA.

ABSTRACT
In the last two years, clinical trials with blocking antibodies to the negative checkpoint regulators CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. Multiple negative checkpoint regulators protect the host against autoimmune reactions but also restrict the ability of T cells to effectively attack tumors. Releasing these brakes has emerged as an exciting strategy for cancer treatment. Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation. In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses. In this review, we describe the current knowledge on the recently discovered negative checkpoint regulators, future targets for immunotherapy.

No MeSH data available.


Related in: MedlinePlus