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Review

Fundamental Mechanisms of Immune Checkpoint Blockade Therapy

Spencer C. Wei, Colm R. Duffy and James P. Allison
Spencer C. Wei
1Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: scwei@mdanderson.org jallison@mdanderson.org
Colm R. Duffy
1Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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James P. Allison
1Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: scwei@mdanderson.org jallison@mdanderson.org
DOI: 10.1158/2159-8290.CD-18-0367 Published September 2018
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    Figure 1.

    Molecular mechanisms of CTLA4 and PD-1 attenuation of T-cell activation. Schematic of the molecular interactions and downstream signaling induced by ligation of CTLA4 and PD-1 by their respective ligands. The possibility of additional downstream cell-intrinsic signaling mechanisms is highlighted for both CTLA4 and PD-1.

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    Figure 2.

    Schematic of the molecular mechanisms of action of CTLA4 and PD-1 blockade. The step-wise progression of T-cell activation, attenuation by normal regulatory mechanisms, and release of such negative regulation by therapeutic intervention using anti-CTLA4 or anti–PD-1 antibodies is outlined (left). In addition to cell-intrinsic enhancement of effector function, several additional mechanisms are thought to contribute to the efficacy of anti-CTLA4 and anti–PD-1 therapy (right). These include antibody-mediated depletion of Tregs, enhancement of T-cell positive costimulation within the tumor microenvironment, blockade of host-derived PD-L1 signals from nontumor cells in the microenvironment (as opposed to tumor cell–derived PD-L1), and blockade of interactions between PD-L1 and B7-1.

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    Figure 3.

    Potential cellular mechanisms that mediate tumor rejection in response to combination anti-CTLA4 and anti–PD-1 checkpoint blockade. Multiple non–mutually exclusive models of the cellular mechanisms underlying combination anti-CTLA4 plus anti–PD-1 therapy of action are proposed. Models described from left to right: (i) the same T cells may be targeted at the site of priming, leading to enhanced penetrance of effective blockade (i.e., a greater proportion of target cells receive sufficient signal to increase activation) and/or enhanced costimulatory signals beyond normal limits, (ii) different T-cell populations are targeted within the site of priming, potentially leading to synergistic effects through cell-extrinsic processes (e.g., providing CD4 help to CD8 effector T cells), (iii) the same T cells are targeted but with different spatiotemporal kinetics leading to perhaps prolonged costimulatory signaling, and (iv) different T-cell populations are targeted in different tissues (e.g., PD-1 blockade primarily acting on preexisting tumor-infiltrating CD8 T cells whereas CTLA4 acts on CD4 effector T cells in secondary lymphoid organs). T-cell subsets are denoted as “A” and “B” given that the precise populations that are directly targeted remain to be fully defined, particularly in the context of kinetics of therapy and different tissue sites. Conceptually, T-cell “A” and “B” could, for example, represent particular subsets of tumor-specific CD8 T cells and CD4 effector T cells, respectively. Potential effects are noted below each scenario; however, there is certain to be additional aggregate effects and differences between these models. Only secondary lymphoid organs (e.g., draining lymph node) and tumor are described, but other tissue sites may have functional contributions to this process as well.

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    Figure 4.

    Potential models of how immune checkpoint blockade restores positive costimulation and modulates T-cell activity. Three non–mutually exclusive theoretical models of how checkpoint blockade regulates the strength of positive costimulation and enhances antitumor immunity. Distinguishing these models will have significant implications for the types and specificities of T cells that are functionally essential for therapeutic efficacy. A, In the first model, checkpoint blockade restores the positive costimulatory signaling to levels similar to those reached prior to attenuation (e.g., by PD-1 or CTLA4). Presumably, in this model, enhanced efficacy due to checkpoint blockade would be primarily derived from an increase in the number of activated and cytolytic T cells. B, In the second model, increased positive costimulation due to blockade of negative costimulatory molecules lowers the effective threshold required for TCR signal strength. This in effect would allow for activation and expansion of weaker T-cell clones (i.e., low-affinity, low-avidity), which are normally restrained. C, In the third model, checkpoint blockade leads to an increase in positive costimulatory signals beyond levels that are achieved in normal scenarios. In this model, enhanced efficacy could be derived from increased number of activated T cells and/or acquisition of new or enhanced functional properties due to super physiologic levels of costimulatory signaling.

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  • Table 1.

    Summary of the tumor types for which immune checkpoint blockade therapies are FDA-approved

    Tumor typeTherapeutic agentFDA approval year
    MelanomaIpilimumab2011
    MelanomaNivolumab2014
    MelanomaPembrolizumab2014
    Non–small cell lung cancerNivolumab2015
    Non–small cell lung cancerPembrolizumab2015
    Melanoma (BRAF wild-type)Ipilimumab + nivolumab2015
    Melanoma (adjuvant)Ipilimumab2015
    Renal cell carcinomaNivolumab2015
    Hodgkin lymphomaNivolumab2016
    Urothelial carcinomaAtezolizumab2016
    Head and neck squamous cell carcinomaNivolumab2016
    Head and neck squamous cell carcinomaPembrolizumab2016
    Melanoma (any BRAF status)Ipilimumab + nivolumab2016
    Non–small cell lung cancerAtezolizumab2016
    Hodgkin lymphomaPembrolizumab2017
    Merkel cell carcinomaAvelumab2017
    Urothelial carcinomaAvelumab2017
    Urothelial carcinomaDurvalumab2017
    Urothelial carcinomaNivolumab2017
    Urothelial carcinomaPembrolizumab2017
    MSI-high or MMR-deficient solid tumors of any histologyPembrolizumab2017
    MSI-high, MMR-deficient metastatic colorectal cancerNivolumab2017
    Pediatric melanomaIpilimumab2017
    Hepatocellular carcinomaNivolumab2017
    Gastric and gastroesophageal carcinomaPembrolizumab2017
    Non–small cell lung cancerDurvalumab2018
    Renal cell carcinomaIpilimumab + nivolumab2018
    • NOTE: A summary of the tumor indications, therapeutic agents, and year of FDA approval for immune checkpoint blockade therapies. FDA approval includes regular approval and accelerated approval granted as of May 2018. Ipilimumab is an anti-CTLA4 antibody. Nivolumab and pembrolizumab are anti–PD-1 antibodies. Atezolizumab, avelumab, and durvalumab are anti–PD-L1 antibodies. Tumor type reflects the indications for which treatment has been approved. Only the first FDA approval granted for each broad tissue type or indication for each therapeutic agent is noted. In cases where multiple therapies received approval for the same tumor type in the same year, agents are listed alphabetically.

    • Abbreviations: MSI, microsatellite instability; MMR, mismatch repair.

  • Table 2.

    Summary of the biological and molecular functions of T-cell costimulatory molecules

    MoleculeLigand(s)Receptor expression patternBiological functionMolecular functionReferences
    Coinhibitory
    CTLA4B7-1 (CD80), B7-2 (CD86)Activated T cells, TregNegative T-cell costimulation (primarily at priming); prevent tonic signaling and/or attenuate high-affinity clonesCompetitive inhibition of CD28 costimulation (binding of B7-1 and B7-2)(8, 10–12, 38, 157–161)
    PD-1PD-L1, PD-L2Activated T cells, NK cells, NKT cells, B cells, macrophages, subsets of DC; as a result of inflammationNegative T-cell costimulation (primarily in periphery); attenuate peripheral activity, preserve T-cell function in the context of chronic antigenAttenuate proximal TCR signaling, attenuate CD28 signaling(32–35, 38, 39, 53, 100, 162–165)
    PD-L1PD-1, B7-1 (CD80)Inducible in DC, monocytes, macrophages, mast cells, T cells, B cells, NK cellsAttenuate T-cell activity in inflamed peripheral tissuesPD-1 ligation; cell-intrinsic mechanism unclear(33, 34, 102)
    LAG3MHC-II, LSECtinActivated CD4 and CD8 T cells, NK cells, TregNegative regulator of T-cell expansion; control T-cell homeostasis; DC activationCompetitive binding to MHC-II; proximal LSECtin mechanism unknown(133, 134, 166–170)
    TIM3Galectin-9, PtdSer, HMGB1, CEACAM-1Th1 CD4 and Tc1 CD8, Treg, DC, NK cells, monocytesNegative regulation of Type 1 immunity; maintain peripheral toleranceNegative regulation of proximal TCR components; differences between ligands unclear(135–139, 171)
    TIGITPVR (CD155), PVRL2 (CD112)CD4 and CD8, Treg, TFH, NK cellsNegative regulation of T-cell activity; DC tolerizationCompetitive inhibition of DNAM1 (CD226) costimulation (binding of PVR), binding of DNAM1 in cis; cell-intrinsic ITIM-negative signaling(144, 145, 172–176)
    VISTACounter-receptor unknownT cells and activated Treg, myeloid cells, mature APCNegative regulation of T-cell activity; suppression of CD4 T cellsIncrease threshold for TCR signaling, induce FOXP3 synthesis; proximal signaling unknown(140, 141, 146, 147, 177, 178)
    Costimulatory
    ICOSICOSLActivated T cells, B cells, ILC2Positive costimulation; Type I and II immune responses; Treg maintenance; TFH differentiationp50 PI3K recruitment (AKT signaling); enhance calcium signaling (PLCγ)(179–186)
    OX40OX40LActivated T cells, Treg, NK cells, NKT cells, neutrophilsSustain and enhance CD4 T-cell responses; role in CD8 T cells and TregsRegulation of BCL2/XL (survival); enhance PI3K/AKT signaling(187–193)
    GITRGITRLActivated T cells, Treg, B cells, NK cells, macrophagesInhibition of Tregs; costimulation of activated T cells, NK cell activationSignal through TRAF5(194–200)
    4-1BB (CD137)4-1BBLActivated T cells, Treg, NK cells, monocytes, DC, B cellsPositive T-cell costimulation; DC activationSignal through TRAF1, TRAF2(201–205)
    CD40CD40LAPCs, B cells, monocytes, nonhematopoietic cells (e.g., fibroblasts, endothelial cells)APC licensingSignal through TRAF2, 3, 5, 6; TRAF-independent mechanisms?(206–209)
    CD27CD70CD4 and CD8 T cells, B cells, NK cellsLymphocyte and NK cell costimulation; generation of T-cell memorySignal through TRAF2, TRAF5(210–214)
    • NOTE: A summary of the ligands, immunologic expression pattern, biological function, and molecular mechanisms is presented for selected costimulatory and coinhibitory receptors. Molecular functions (i.e., downstream signaling) reflect predominant currently known mechanisms, but additional mechanisms are likely to contribute significantly.

    • Abbreviations: NK, natural killer; NKT, natural killer T cell; TFH, T follicular helper; TRAF, tumor necrosis factor receptor–associated factors; DC, dendritic cell.

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Cancer Discovery: 8 (9)
September 2018
Volume 8, Issue 9
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Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
Spencer C. Wei, Colm R. Duffy and James P. Allison
Cancer Discov September 1 2018 (8) (9) 1069-1086; DOI: 10.1158/2159-8290.CD-18-0367

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Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
Spencer C. Wei, Colm R. Duffy and James P. Allison
Cancer Discov September 1 2018 (8) (9) 1069-1086; DOI: 10.1158/2159-8290.CD-18-0367
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  • Article
    • Abstract
    • Introduction
    • Mechanisms of CTLA4-Mediated Negative Costimulation
    • Mechanisms of PD-1–Mediated Attenuation of T-Cell Activity
    • Mechanisms of Negative Costimulation Versus Mechanisms of Checkpoint Blockade
    • Mechanisms of Action of CTLA4 Blockade–Induced Tumor Rejection
    • Mechanisms of Action of PD-1 Blockade–Induced Tumor Rejection
    • Therapeutic Combinations
    • Beyond CTLA4 and PD-1
    • Concluding Remarks
    • Disclosure of Potential Conflicts of Interest
    • Acknowledgments
    • References
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