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Cancer Immune Checkpoints

Written/Edited by Julian Pampel, BSc

Immune checkpoints are receptors on the membrane of T-lymphocytes that can regulate their immune response. They are refinely tuned and alternate between stimulation and inhibition1. The immuno checkpoints pathway is crucial to promote self-tolerance and prevent autoimmunity and related diseases.
T-cell receptors are in focus of medical research, however, global immunosuppression greatly increases the risk of acquiring life-threatening infections and is associated with organ toxicity when used long-term. Thus, alternative approaches that inhibit only the unwanted immune responses and preserve general immunity are highly desirable. The tumor necrosis factor (TNF) receptor superfamily represents the largest part of receptors with CD27, CD40, OX40, GITR and CD137. Two additional stimulatory checkpoint molecules belong to the B7-CD28 superfamily: CD28 itself and ICOS.1

Co-Stimulation and Inhibition with BTLA and HVEM: The HVEM/ LIGHT/BTLA/CD160 costimulatory/coinhibitory pathway has emerged as a potential target for the development of immune therapeutic interventions. The interaction between BTLA, short for B and T Lymphocyte Attenuator, an inhibitory receptor whose extracellular domain belongs to the immunoglobulin superfamily, and herpesvirus-entry mediator (HVEM), a co-stimulatory tumour-necrosis factor receptor, is unique in that it is the only receptor–ligand interaction that directly links these two families of receptors.2 Recent studies show that engagement of HVEM with its endogenous ligand (LIGHT) from the tumour-necrosis factor family induces a powerful immune response. LIGHT stimulates the proliferation of T cells, and triggers apoptosis of various tumor cells, whereas HVEM interactions with BTLA negatively regulate T-cell responses.3

Importance of Checkpoint Inhibitors for Cancer Immunotherapy: Inhibitory checkpoint molecules are promising targets for cancer immunotherapy. The discovery and clinical application of immune-checkpoint inhibitors has dramatically improved the treatments, outcomes and therapeutic concepts in multiple tumor settings. Of the immune checkpoint proteins identified to date, CTLA-4 is a critical regulator of T-cell responses4. CTLA-4 is structurally similar to the co-stimulating receptor CD28, with both receptors also binding to CD80 and CD86 (also known as B7-1 and B7-2). Binding to CD80 or CD86 leads to a competition between an inhibitory signal (by CTLA-4) and a co-stimulating signal (by CD28). In 2018 the research on monoclonal antibodies blocking the inhibitory molecule CTLA-4 and or the PD-1/PD-L1 axis by James P. Allison & Tasuku Honjo, was awarded with The Nobel Prize in Physiology or Medicine.5


References:

  1. Hughes, Bundred: "Breast macrocysts." in: World journal of surgery, Vol. 13, Issue 6, pp. 711-4, (1990) (PubMed).
  2. Murphy, Nelson, Sedý: "Balancing co-stimulation and inhibition with BTLA and HVEM." in: Nature reviews. Immunology, Vol. 6, Issue 9, pp. 671-81, (2006) (PubMed).
  3. del Rio, Fernandez-Renedo, Chaloin, Scheu, Pfeffer, Shintani, Perez-Simon, Schneider, Rodriguez-Barbosa: "Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells." in: mAbs, Vol. 8, Issue 3, pp. 478-90, (2016) (PubMed).
  4. Rowshanravan, Halliday, Sansom: "CTLA-4: a moving target in immunotherapy." in: Blood, Vol. 131, Issue 1, pp. 58-67, (2018) (PubMed).

References:

  • (5) James P. Allison and Tasuku Honjo : “for their discovery of cancer therapy by inhibition of negative immune regulation”. The Nobel Assembly at Karolinska Institutet (2018). [Press Release]

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Inhibitory T-Cell Receptors

LAG3 (Lymphocyte-Activation Gene 3):

VISTA (V-type immunoglobulin domain-containing suppressor of T-cell activation):

TIGIT (T Cell Immunoreceptor with Ig and ITIM Domains):

BTLA (B and T Lymphocyte Associated):

KIR2DL3 (Killer Cell Immunoglobulin-Like Receptor, Two Domains, Long Cytoplasmic Tail, 3):

TIMD4 (T-Cell Immunoglobulin and Mucin Domain Containing 4):

TNFSF14 (Tumor Necrosis Factor (Ligand) Superfamily, Member 14):

Major Histocompatibility Complex

HLA-A (Major Histocompatibility Complex, Class I, A):

MR1 (Major Histocompatibility Complex, Class I-Related):

CIITA (Class II, Major Histocompatibility Complex, Transactivator):

HLAG (HLA Class I Histocompatibility Antigen, alpha Chain G):

HLA-B (Major Histocompatibility Complex, Class I, B):

HLA-ABC (HLA-ABC):

HLA-DMA (Major Histocompatibility Complex, Class II, DM alpha):

HLA-DMB (Major Histocompatibility Complex, Class II, DM beta):

HLA-DOB (Major Histocompatibility Complex, Class II, DO beta):

HLA-DPA1 (Major Histocompatibility Complex, Class II, DP alpha 1):

HLA-DPB1 (Major Histocompatibility Complex, Class II, DP beta 1):

HLA-DQA1 (Major Histocompatibility Complex, Class II, DQ alpha 1):

HLA-DQB1 (Major Histocompatibility Complex, Class II, DQ beta 1):

HLA-DRB1 (Major Histocompatibility Complex, Class II, DR beta 1):

HLA-DRB3 (Major Histocompatibility Complex, Class II, DR beta 3):

HLA-DRB5 (Major Histocompatibility Complex, Class II, DR beta 5):

PTCRA (Pre T-Cell Antigen Receptor alpha):

Stimulatory T-Cell Receptors

CTLA4 (Cytotoxic T-Lymphocyte-Associated Protein 4):

TNFSF4 (Tumor Necrosis Factor (Ligand) Superfamily, Member 4):

ACVR2B (Activin A Receptor, Type IIB):

ICOS (Inducible T-Cell Co-Stimulator):

TNFSF9 (Tumor Necrosis Factor (Ligand) Superfamily, Member 9):

TNFRSF18 (Tumor Necrosis Factor Receptor Superfamily, Member 18):

TNFRSF4 (Tumor Necrosis Factor Receptor Superfamily, Member 4):

Cytokines

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