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Immune Checkpoint Signaling in the Tumor Microenvironment

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Pathway Description:

Immune checkpoints refer to the inbuilt control mechanisms of the immune system that maintain self-tolerance and help to avoid collateral damage during a physiological immune response. It is now evident that tumors engineer microenvironments to evade immune surveillance and attack, particularly by modulating certain immune-checkpoint pathways.

Under normal physiological conditions, CD8+ cytotoxic T lymphocytes and CD4+ helper T cells are activated through the interaction of T cell receptors (TCRs) with peptide antigens bound to major histocompatibility complex (MHC) molecules presented on the surface of antigen-presenting cells (APCs). Ligand/receptor interactions through co-stimulatory molecules expressed by T cells (ex. CD28, 4-1BB, OX40, GITR, ICOS) and APCs (ex. CD80, CD86, 4-1BBL, OX40L, GITRL, ICOSLG) are also required for optimal T cell activation. Conversely, T cell activation can be suppressed by co-inhibitory signaling through interactions between receptors, such as PD-1, CTLA-4, TIM-3, and LAG3 expressed on T Cells, and their respective ligands expressed on APCs and other cells of the microenvironment. For example, interactions between PD-L1 or PD-L2 and the PD-1 receptor result in downregulation of TCR signaling in T cells through dephosphorylation of major components of the T Cell Receptor Signaling Pathway. CTLA-4, a co-inhibitory receptor, competes with CD28, a co-stimulatory receptor, to interact with CD80 and CD86 ligands on APCs. Upon receptor/ligand interaction, CTLA-4 inhibits T cell proliferation, cell cycle progression, and cytokine production, whereas CD28 is required for T cell activation.

Within the tumor microenvironment, cancer cells have co-opted inhibitory ligands and their receptors that regulate T cell effector function in order to enhance tumor tolerance and evade eradication by the immune system. In recent years, pharmacological modulators of these pathways, known as immune checkpoint therapies, particularly in the form of monoclonal antibodies against PD-1 and CTLA-4, have been intensely researched and deployed as novel immunotherapy agents to treat cancers. Given the early success of immune checkpoint therapies, creating immunotherapies targeting other co-inhibitory and co-stimulatory receptors and their ligands in order to activate anti-tumor immune responses appears to be a compelling therapeutic strategy.

Selected Reviews:

  • Smith-garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol. 2009;27:591-619.
  • Nirschl CJ, Drake CG. Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy. Clin Cancer Res. 2013;19(18):4917-24.
  • Aspeslagh S, Postel-vinay S, Rusakiewicz S, Soria JC, Zitvogel L, Marabelle A. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016;52:50-66.
  • Schildberg FA, Klein SR, Freeman GJ, Sharpe AH. Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity. 2016;44(5):955-72.
  • Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 2013;34(11):556-63.
  • Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219-42.
  • Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer. 2012;12(4):252-264.
  • Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56-61
  • Sagiv-barfi I, Czerwinski DK, Levy S, et al. Eradication of spontaneous malignancy by local immunotherapy. Sci Transl Med. 2018;10(426)
created March 2018
  • KinaseKinase
  • PhosphatasePhosphatase
  • Transcription FactorTranscription Factor
  • CaspaseCaspase
  • ReceptorReceptor
  • EnzymeEnzyme
  • pro-apoptoticpro-apoptotic
  • pro-survivalpro-survival
  • GTPaseGTPase
  • G-proteinG-protein
  • AcetylaseAcetylase
  • DeacetylaseDeacetylase
  • Ribosomal subunitRibosomal subunit
  • Direct Stimulatory ModificationDirect Stimulatory Modification
  • Direct Inhibitory ModificationDirect Inhibitory Modification
  • Multistep Stimulatory ModificationMultistep Stimulatory Modification
  • Multistep Inhibitory ModificationMultistep Inhibitory Modification
  • Tentative Stimulatory ModificationTentative Stimulatory Modification
  • Tentative Inhibitory ModificationTentative Inhibitory Modification
  • Separation of Subunits or Cleavage ProductsSeparation of Subunits or Cleavage Products
  • Joining of SubunitsJoining of Subunits
  • TranslocationTranslocation
  • Transcriptional Stimulatory ModificationTranscriptional Stimulatory Modification
  • Transcriptional Inhibitory ModificationTranscriptional Inhibitory Modification