Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies

Abstract The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Å resolution. A central FDPPPF motif and residues within the CC’ loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors.

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Relaxin-expressing oncolytic adenovirus induces remodeling of physical and immunological aspects of cold tumor to potentiate PD-1 blockade

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000763 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000763 ◽

Cited By ~ 2

Author(s):

Bo-Kyeong Jung ◽

Hae Young Ko ◽

Hyunji Kang ◽

JinWoo Hong ◽

Hyo Min Ahn ◽

...

Keyword(s):

Combination Therapy ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Oncolytic Adenovirus ◽

Therapeutic Effects ◽

Tumor Models ◽

Activated T Cells ◽

Therapy Regimen ◽

Gm Csf ◽

Positron Emission

BackgroundCurrently, several antibody (Ab)-based therapies have shown excellent therapeutic effects in the clinic. Nonetheless, Ab penetration into tumor tissues is limited due to abnormal vasculature, tumor interstitial pressure, and excessive extracellular matrix (ECM) accumulation, thus demanding novel strategies to overcome these barriers.MethodsThe intratumoral distribution of therapeutic Abs were detected by fluorescence microscopy or positron emission tomography in both human gastric xenograft and syngeneic pancreatic hamster tumor models. The antitumor efficacy by combination of oncolytic adenovirus (Ad), which coexpresses relaxin (RLX), interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor (GM-CSF) (oAd/IL12/GM-RLX) and antibody against the programmed cell death protein 1 (αPD-1) was examined in hamster subcutaneous and orthotopic pancreatic tumor models. The immunological aspects of these combination therapy regimen were assessed by flow cytometry or immunohistochemistry in subcutaneous hamster tumor models.ResultsRelaxin-expressing oncolytic Ad effectively degraded tumor ECM and enhanced the tumor penetration of trastuzumab in comparison with trastuzumab monotherapy. Based on these results, an oAd/IL12/GM-RLX was used to enhance the potency of immune checkpoint blockade. The combination of the oAd/IL12/GM-RLX and αPD-1 promoted a concomitant degradation of the tumor ECM and amelioration of the immunosuppressive tumor niches, ultimately enhanced intratumoral infiltration of both αPD-1 and activated T cells. Of note, the combination therapy was able to elicit a potent and durable antitumor immune response against cold tumors that were refractory to immune checkpoint inhibitor monotherapy.ConclusionsOur findings are the first to demonstrate that expression of four genes (IL-12p35, IL-12p40, GM-CSF, and RLX) mediated by a single oncolytic Ad vector can promote remodeling of both physical and immunological aspects of the tumor niches to overcome the major limitations of Ab-based therapies that have emerged in recent clinical trials.

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Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses

Communications Biology ◽

10.1038/s42003-020-1083-1 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Asiel A. Benitez ◽

Sara Khalil-Agüero ◽

Anjali Nandakumar ◽

Namita T. Gupta ◽

Wen Zhang ◽

...

Keyword(s):

T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Tumor Rejection ◽

Checkpoint Blockade ◽

Cell Repertoire ◽

Activated T Cells ◽

Central Tolerance ◽

Tolerance Breakdown ◽

Deficient Mice

AbstractThe endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models, was accompanied by increased numbers of activated T cells expressing high levels of Gzma, Gzmb, Perforin, Cxcr3, and increased intratumoural levels of Cxcl9 and Cxcl10 compared to wild-type mice. Consistent with Aire’s central role in T cell repertoire selection, single cell TCR sequencing unveiled expansion of several clones with high tumor reactivity. The data suggest that breakdown in central tolerance synergizes with immune checkpoint blockade in enhancing anti-tumor immunity and may serve as a model to unmask novel anti-tumor therapies including anti-tumor TCRs, normally purged during central tolerance.

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Combinatorial Approach to Improve Cancer Immunotherapy: Rational Drug Design Strategy to Simultaneously Hit Multiple Targets to Kill Tumor Cells and to Activate the Immune System

Journal of Oncology ◽

10.1155/2019/5245034 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18 ◽

Cited By ~ 33

Author(s):

Shweta Joshi ◽

Donald L. Durden

Keyword(s):

Cancer Immunotherapy ◽

Immune Checkpoint ◽

Therapeutic Potential ◽

Checkpoint Inhibitors ◽

Clinical Success ◽

Immune Checkpoint Blockade ◽

Rational Drug Design ◽

Therapeutic Interventions ◽

Epigenetic Therapy ◽

T Cell Therapy

Cancer immunotherapy, including immune checkpoint blockade and adoptive CAR T-cell therapy, has clearly established itself as an important modality to treat melanoma and other malignancies. Despite the tremendous clinical success of immunotherapy over other cancer treatments, this approach has shown substantial benefit to only some of the patients while the rest of the patients have not responded due to immune evasion. In recent years, a combination of cancer immunotherapy together with existing anticancer treatments has gained significant attention and has been extensively investigated in preclinical or clinical studies. In this review, we discuss the therapeutic potential of novel regimens combining immune checkpoint inhibitors with therapeutic interventions that (1) increase tumor immunogenicity such as chemotherapy, radiotherapy, and epigenetic therapy; (2) reverse tumor immunosuppression such as TAMs, MDSCs, and Tregs targeted therapy; and (3) reduce tumor burden and increase the immune effector response with rationally designed dual or triple inhibitory chemotypes.

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Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade

Science Translational Medicine ◽

10.1126/scitranslmed.aat5025 ◽

2019 ◽

Vol 11 (515) ◽

pp. eaat5025 ◽

Cited By ~ 17

Author(s):

Tala Shekarian ◽

Eva Sivado ◽

Anne-Catherine Jallas ◽

Stéphane Depil ◽

Janice Kielbassa ◽

...

Keyword(s):

Targeted Therapies ◽

Immune Checkpoint ◽

Genetically Modified Organisms ◽

Immune Checkpoint Blockade ◽

Oncolytic Viruses ◽

Therapeutic Interventions ◽

Antitumor Effects ◽

Rotavirus Vaccines

Although immune checkpoint–targeted therapies are currently revolutionizing cancer care, only a minority of patients develop durable objective responses to anti–PD-1, PD-L1, and CTLA-4 therapy. Therefore, new therapeutic interventions are needed to increase the immunogenicity of tumors and overcome the resistance to these immunotherapies. Oncolytic properties of common viruses can be exploited for the priming of antitumor immunity, and such oncolytic viruses are currently in active clinical development in combination with immune checkpoint–targeted therapies. However, the routine implementation of these therapies is limited by their manufacturing constraints, the risk of exposure of clinical staff, and the ongoing regulations on genetically modified organisms. We sought to determine whether anti-infectious disease vaccines could be used as a commercially available source of immunostimulatory agents for cancer immunotherapy. We found that rotavirus vaccines have both immunostimulatory and oncolytic properties. In vitro, they can directly kill cancer cells with features of immunogenic cell death. In vivo, intratumoral rotavirus therapy has antitumor effects that are dependent on the immune system. In several immunocompetent murine tumor models, intratumoral rotavirus overcomes resistance to and synergizes with immune checkpoint–targeted therapy. Heat- and UV-inactivated rotavirus lost their oncolytic activity but kept their synergy with immune checkpoint–targeted antibodies through the up-regulation of the double-stranded RNA receptor retinoic acid–induced gene 1 (RIG-I). Rotavirus vaccines are clinical-grade products used in pediatric and adult populations. Therefore, in situ immunization strategies with intratumoral-attenuated rotavirus could be implemented quickly in the clinic.

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The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy

ESMO Open ◽

10.1136/esmoopen-2019-000544 ◽

2020 ◽

Vol 5 (1) ◽

pp. e000544 ◽

Cited By ~ 5

Author(s):

Cinzia Solinas ◽

Chunyan Gu-Trantien ◽

Karen Willard-Gallo

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

T Cell Activation ◽

Immune Checkpoint ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Immune Checkpoint Blockade ◽

Activated T Cells

Inducible T cell costimulator (ICOS, cluster of differentiation (CD278)) is an activating costimulatory immune checkpoint expressed on activated T cells. Its ligand, ICOSL is expressed on antigen-presenting cells and somatic cells, including tumour cells in the tumour microenvironment. ICOS and ICOSL expression is linked to the release of soluble factors (cytokines), induced by activation of the immune response. ICOS and ICOSL binding generates various activities among the diversity of T cell subpopulations, including T cell activation and effector functions and when sustained also suppressive activities mediated by regulatory T cells. This dual role in both antitumour and protumour activities makes targeting the ICOS/ICOSL pathway attractive for enhancement of antitumour immune responses. This review summarises the biological background and rationale for targeting ICOS/ICOSL in cancer together with an overview of the principal ongoing clinical trials that are testing it in combination with anti-cytotoxic T lymphocyte antigen-4 and anti-programmed cell death-1 or anti-programmed cell death ligand-1 based immune checkpoint blockade.

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Tumour neoantigen mimicry by microbial species in cancer immunotherapy

British Journal of Cancer ◽

10.1038/s41416-021-01365-2 ◽

2021 ◽

Author(s):

Maximilian Boesch ◽

Florent Baty ◽

Sacha I. Rothschild ◽

Michael Tamm ◽

Markus Joerger ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Immune Checkpoint ◽

Molecular Mimicry ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Molecular Fingerprint ◽

Microbial Species ◽

Anti Cancer

AbstractTumour neoantigens arising from cancer-specific mutations generate a molecular fingerprint that has a definite specificity for cancer. Although this fingerprint perfectly discriminates cancer from healthy somatic and germline cells, and is therefore therapeutically exploitable using immune checkpoint blockade, gut and extra-gut microbial species can independently produce epitopes that resemble tumour neoantigens as part of their natural gene expression programmes. Such tumour molecular mimicry is likely not only to influence the quality and strength of the body’s anti-cancer immune response, but could also explain why certain patients show favourable long-term responses to immune checkpoint blockade while others do not benefit at all from this treatment. This article outlines the requirement for tumour neoantigens in successful cancer immunotherapy and draws attention to the emerging role of microbiome-mediated tumour neoantigen mimicry in determining checkpoint immunotherapy outcome, with far-reaching implications for the future of cancer immunotherapy.

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Acquired Resistance to Immune Checkpoint Blockade Therapies

Cancers ◽

10.3390/cancers12051161 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1161

Author(s):

Xianda Zhao ◽

Dechen Wangmo ◽

Matthew Robertson ◽

Subbaya Subramanian

Keyword(s):

Immune Checkpoint ◽

Cell Function ◽

Immune Cell ◽

Current Knowledge ◽

Clinical Investigation ◽

Acquired Resistance ◽

Genomic Analysis ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Response To Treatment

Immune checkpoint blockade therapy (ICBT) has revolutionized the treatment and management of numerous cancers, yet a substantial proportion of patients who initially respond to ICBT subsequently develop resistance. Comprehensive genomic analysis of samples from recent clinical trials and pre-clinical investigation in mouse models of cancer provide insight into how tumors evade ICBT after an initial response to treatment. Here, we summarize our current knowledge on the development of acquired ICBT resistance, by examining the mechanisms related to tumor-intrinsic properties, T-cell function, and tumor-immune cell interactions. We discuss current and future management of ICBT resistance, and consider crucial questions remaining in this field of acquired resistance to immune checkpoint blockade therapies.

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