Cancer immunoediting and resistance to T cell-based immunotherapy

Nature Reviews Clinical Oncology, Journal Year: 2018, Volume and Issue: 16(3), P. 151 - 167

Published: Dec. 6, 2018

Language: Английский

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Mechanisms of resistance to immune checkpoint inhibitors

British Journal of Cancer, Journal Year: 2018, Volume and Issue: 118(1), P. 9 - 16

Published: Jan. 1, 2018

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer are rapidly transforming practice medical oncology. Whereas cytotoxic chemotherapy small molecule ('targeted therapies') largely act on cells directly, immune reinvigorate anti-tumour responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops patients treated with conventional therapies targeted therapies, durable suggestive long-lasting immunologic memory commonly seen large subsets ICI. However, initial response appears to be a binary event, most non-responders single-agent ICI therapy progressing at rate consistent natural history disease. In addition, late relapses now emerging longer follow-up trial populations, suggesting emergence acquired resistance. As robust biomarkers predict and/or remain elusive, mechanisms underlying innate (primary) (secondary) inferred from pre-clinical studies correlative data. Improved understanding molecular (and resistance) may not only identify novel predictive prognostic biomarkers, but also ultimately guide optimal combination/sequencing clinic. Here we review data identifying inhibition.

Language: Английский

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Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids

Cancer Discovery, Journal Year: 2017, Volume and Issue: 8(2), P. 196 - 215

Published: Nov. 4, 2017

Ex vivo systems that incorporate features of the tumor microenvironment and model dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology development effective combination therapies. Here, we demonstrate ability interrogate ex ICB using murine- patient-derived organotypic spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse human tumors retain autologous lymphoid myeloid cell populations respond short-term three-dimensional microfluidic culture. Response resistance was recapitulated MDOTS derived established immunocompetent models. profiling demonstrated TBK1/IKKε inhibition enhanced PD-1 blockade, which effectively predicted Systematic secreted cytokines PDOTS captured key associated with blockade. Thus, represents a novel platform evaluate murine models as well clinically relevant patient specimens.Significance: Resistance remains challenge for many patients, biomarkers guide treatment are lacking. feasibility microenvironment, develop therapeutic combinations, efforts. Cancer Discov; 8(2); 196-215. ©2017 AACR.See related commentary by Balko Sosman, p. 143See article Deng et al., 216This is highlighted In This Issue feature, 127.

Language: Английский

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Application of PD-1 Blockade in Cancer Immunotherapy

Computational and Structural Biotechnology Journal, Journal Year: 2019, Volume and Issue: 17, P. 661 - 674

Published: Jan. 1, 2019

The programmed cell death protein 1 (PD-1) pathway has received considerable attention due to its role in eliciting the immune checkpoint response of T cells, resulting tumor cells capable evading surveillance and being highly refractory conventional chemotherapy. Application anti-PD-1/PD-L1 antibodies as inhibitors is rapidly becoming a promising therapeutic approach treating tumors, some them have successfully been commercialized past few years. However, not all patients show complete responses adverse events noted, suggesting better understanding PD-1 mediated immunosuppression needed predict patient improve treatment efficacy. Here, we review progresses on studies mechanistic evasion, recent clinical development commercialization inhibitors, toxicities associated with blockade observed trials well how efficacy safety cancer immunotherapy.

Language: Английский

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Resistance to Systemic Therapies in Clear Cell Renal Cell Carcinoma: Mechanisms and Management Strategies

Molecular Cancer Therapeutics, Journal Year: 2018, Volume and Issue: 17(7), P. 1355 - 1364

Published: July 1, 2018

Abstract Renal cell carcinoma (RCC) is the most common form of kidney cancer. It categorized into various subtypes, with clear RCC (ccRCC) representing about 85% all tumors. The lack sensitivity to chemotherapy and radiation therapy prompted research efforts novel treatment options. development targeted therapeutics, including multi-targeted tyrosine kinase inhibitors (TKI) mTOR inhibitors, has been a major breakthrough in ccRCC therapy. More recently, other therapeutic strategies, immune checkpoint have emerged as effective options against advanced ccRCC. Furthermore, recent advances disease biology, tumor microenvironment, mechanisms resistance formed basis for attempts combine therapies newer generation immunotherapies take advantage possible synergy. This review focuses on current status basic, translational, clinical studies systemic Mol Cancer Ther; 17(7); 1355–64. ©2018 AACR.

Language: Английский

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New insights into the role of EMT in tumor immune escape

Molecular Oncology, Journal Year: 2017, Volume and Issue: 11(7), P. 824 - 846

Published: June 14, 2017

Novel immunotherapy approaches have provided durable remission in a significant number of cancer patients with cancers previously considered rapidly lethal. Nonetheless, the high degree nonresponders, and some cases emergence resistance who do initially respond, represents challenge field immunotherapy. These issues prompt much more extensive studies to better understand how cells escape immune surveillance resist attacks. Here, we review current knowledge cellular heterogeneity plasticity could be involved shaping tumor microenvironment (TME) controlling antitumor immunity. Indeed, recent findings led increased interest mechanisms by which undergoing epithelial-mesenchymal transition (EMT), or oscillating within EMT spectrum, might contribute through multiple routes. This includes TME decreased susceptibility effector cells. Although remains learned on at play, cell clones mesenchymal features emerging from seem primed face attacks specialized killer system, natural cells, cytotoxic T lymphocytes. Recent investigating patient tumors suggested as candidate predictive marker explored for outcome. Promising data also exist potential utility targeting these populations least partly overcome such resistance. Research is now underway may lead considerable progress optimization treatments.

Language: Английский

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Dendritic cell biology and its role in tumor immunotherapy

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: Aug. 3, 2020

Abstract As crucial antigen presenting cells, dendritic cells (DCs) play a vital role in tumor immunotherapy. Taking into account the many recent advances DC biology, we discuss how DCs (1) recognize pathogenic antigens with pattern recognition receptors through specific phagocytosis and non-specific micropinocytosis, (2) process small peptides proper sizes sequences, (3) present MHC-peptides to CD4 + CD8 T initiate immune responses against invading microbes aberrant host cells. During anti-tumor responses, DC-derived exosomes were discovered participate presentation. cell microvillar dynamics TCR conformational changes demonstrated upon Caspase-11-driven hyperactive recently reported convert effectors memory also crosstalk NK Additionally, are most important sentinel for surveillance microenvironment. Alongside review latest developments DC-based immunotherapy preclinical studies clinical trials. Personalized vaccine-induced immunity, which targets tumor-specific antigens, has been be promising form of patients melanoma. Importantly, allogeneic-IgG-loaded HLA-restricted neoantigen vaccines have robust effects mice. Our comprehensive biology its aids understanding as mentors novel immense potential.

Language: Английский

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PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 1, 2021

Programmed death protein 1 (PD1) is a common immunosuppressive member on the surface of T cells and plays an imperative part in downregulating immune system advancing self-tolerance. Its ligand programmed cell (PDL1) overexpressed malignant tumor cells, where it binds to PD1, inhibits proliferation PD1-positive participates evasion tumors leading treatment failure. The PD1/PDL1-based pathway great value immunotherapy cancer has become important checkpoint recent years, so understanding mechanism PD1/PDL1 action significance for combined patient prognosis. inhibitors have shown clinical efficacy many tumors, example, blockade PD1 or PDL1 with specific antibodies enhances responses mediates antitumor activity. However, some patients are prone develop drug resistance, resulting poor outcomes, which rooted insensitivity targeted inhibitors. In this paper, we reviewed application immunotherapy. We hope that future, promising combination therapy regimens can be developed allow immunotherapeutic tools play role treatment. also discuss safety issues further reflect effectiveness side effects brings.

Language: Английский

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Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: May 27, 2021

The tumor microenvironment (TME) is a complex and ever-changing “rogue organ” composed of its own blood supply, lymphatic nervous systems, stroma, immune cells extracellular matrix (ECM). These components, utilizing both benign malignant cells, nurture the harsh, immunosuppressive nutrient-deficient environment necessary for cell growth, proliferation phenotypic flexibility variation. An important aspect TME cellular crosstalk cell-to-ECM communication. This interaction induces release soluble factors responsible evasion ECM remodeling, which further contribute to therapy resistance. Other aspects are presence exosomes contributed by circulating deregulated microRNAs TME-specific metabolic patterns potentiate progression and/or resistance therapy. In addition biochemical signaling, specific characteristics such as hypoxic environment, derangements, abnormal mechanical forces have been implicated in development treatment this review, we will provide an overview microenvironmental composition, structure, features that influence suppression

Language: Английский

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Treatment of Advanced Melanoma in 2020 and Beyond

Journal of Investigative Dermatology, Journal Year: 2020, Volume and Issue: 141(1), P. 23 - 31

Published: April 5, 2020

Language: Английский

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