Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Bakhru, Pearl; Zhu, Meng-Lei; Wang, Hsing-Hui; Hong, Lee K.; Khan, Imran S.; Mouchess, Maria L.; Gulati, Ajay; Starmer, Joshua; Hou, Yayi; Sailer, David; Lee, Sandra; Zhao, Fengmin; Kirkwood, John M.; Moschos, Stergios J.; Fong, Lawrence; Anderson, Mark S.; Su, Maureen A.

doi:10.1172/jci.insight.93265

Cited by 41 publications

(35 citation statements)

References 55 publications

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“…The dichotomy in clinical presentation and disease onset and severity of these two monogenic diseases illustrates that although AIRE regulates thymic Treg generation through positive selection, the development of autoreactive CD4 + effector T cells may play a primary role in the pathogenesis in APECED patients. Beyond the important role of these AIRE‐dependent functions in induction of tolerance and prevention of autoimmunity, there is emerging literature on how therapeutic manipulation of the Aire‐dependent thymic development of tumor‐associated Tregs and of the Aire‐dependent negative selection of tumor‐specific effector T cells may have implications in designing novel anti‐tumor therapeutic strategies …”

Section: Aire Expression and Functionmentioning

confidence: 99%

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Constantine

Lionakis

2018

Immunological Reviews

128

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Summary: The discovery of the Autoimmune Regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.

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Section: Aire Expression and Functionmentioning

confidence: 99%

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Constantine

Lionakis

2018

Immunological Reviews

128

View full text Add to dashboard Cite

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“…RANKL inhibition can reversibly decrease self-antigen expression in the thymus and can spare from deletion T cells that target melanoma, thus enhancing the anti-tumour immune response and improving survival [76]. Furthermore, synergy has been observed between the suppression of central tolerance in Aire-deficient mice and peripheral immune checkpoint inhibition using anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies with respect to slowing tumour growth and improving survival through increasing T cells that target melanoma [77]. Co-treatment with anti-RANKL and anti-CTLA-4 antibodies could not reproduce the synergistic effect of Aire-deficiency and anti-CTLA-4 antibodies on survival, although synergistic improvements in survival with co-treatment could be achieved if mice were also vaccinated with tumour cells producing granulocyte-macrophage colony-stimulating factor [77].…”

Section: Potential Immunomodulatory Role Of Rank-rankl Signallingmentioning

confidence: 99%

The RANK–RANKL axis: an opportunity for drug repurposing in cancer?

et al. 2019

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Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

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“…thymic) or peripheral (e.g. tissue) tolerance; [77][78][79][80][81][82][83][84][85][86] (3) the relatively limited avidity of TAA-specific (and sometimes also TSA-specific) TCRs; [87][88][89][90][91][92][93][94][95][96] and (4) the ability of cancer cells to compromise cellular fitness and/or effector functions of T cells, hence driving 'exhaustion' or 'anergy'. [97][98][99][100][101][102][103][104][105][106][107][108][109] Two main criteria should be met for any treatment modality to be classified as a bona fide ICD inducer.…”

Section: Introductionmentioning

confidence: 99%

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

et al. 2020

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The term 'immunogenic cell death' (ICD) denotes an immunologically unique type of regulated cell death that enables, rather than suppresses, T cell-driven immune responses that are specific for antigens derived from the dying cells. The ability of ICD to elicit adaptive immunity heavily relies on the immunogenicity of dying cells, implying that such cells must encode and present antigens not covered by central tolerance (antigenicity), and deliver immunostimulatory molecules such as damage-associated molecular patterns and cytokines (adjuvanticity). Moreover, the host immune system must be equipped to detect the antigenicity and adjuvanticity of dying cells. As cancer (but not normal) cells express several antigens not covered by central tolerance, they can be driven into ICD by some therapeutic agents, including (but not limited to) chemotherapeutics of the anthracycline family, oxaliplatin and bortezomib, as well as radiation therapy. In this Trial Watch, we describe current trends in the preclinical and clinical development of ICD-eliciting chemotherapy as partner for immunotherapy, with a focus on trials assessing efficacy in the context of immunomonitoring.

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Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Cited by 41 publications

References 55 publications

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

The RANK–RANKL axis: an opportunity for drug repurposing in cancer?

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

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