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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mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern

Science, Journal Year: 2021, Volume and Issue: 374(6572)

Published: Oct. 15, 2021

Immune memory after vaccination Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven highly effective at preventing COVID-19. However, the evolution of viral variants, and waning antibody levels over time, raise questions regarding longevity vaccine-induced immune protection. Goel et al . examined B T lymphocyte responses in individuals who received SARS-CoV-2 messenger RNA vaccines. They performed a 6-month longitudinal study never had infection compared with people recovered from SARS-CoV-2. Humoral cellular was observed vaccinated individuals, as were functional Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2) variants. Analysis cell activity suggested that robust may prevent hospitalization by limiting development disease. —PNK

Language: Английский

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Therapeutic T cell engineering

Nature, Journal Year: 2017, Volume and Issue: 545(7655), P. 423 - 431

Published: May 23, 2017

Language: Английский

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Quantifying Memory CD8 T Cells Reveals Regionalization of Immunosurveillance

Cell, Journal Year: 2015, Volume and Issue: 161(4), P. 737 - 749

Published: May 1, 2015

Memory CD8 T cells protect against intracellular pathogens by scanning host cell surfaces; thus, infection detection rates depend on memory number and distribution. Population analyses rely isolation from whole organs, interpretation is predicated presumptions of near complete recovery. Paradigmatically, parsed into central, effector, resident subsets, ostensibly defined immunosurveillance patterns but in practice identified phenotypic markers. Because methods ultimately inform models differentiation, protection, vaccine translation, we tested their validity via parabiosis quantitative immunofluorescence microscopy a mouse population. We report three major findings: lymphocyte fails to recover most biases certain residents greatly outnumber recirculating within non-lymphoid tissues, subset homing inflammation does not conform previously hypothesized migration patterns. These results indicate that are surveyed for reinfection segregated rather than migrate throughout the blood body.

Language: Английский

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Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Oct. 17, 2019

Human T cells coordinate adaptive immunity in diverse anatomic compartments through production of cytokines and effector molecules, but it is unclear how tissue site influences cell persistence function. Here, we use single RNA-sequencing (scRNA-seq) to define the heterogeneity human isolated from lungs, lymph nodes, bone marrow blood, their functional responses following stimulation. Through analysis >50,000 resting activated cells, reveal signatures mucosal lymphoid sites, lineage-specific activation states across all sites including distinct for CD8+ an interferon-response state CD4+ cells. Comparing scRNA-seq profiles tumor-associated our dataset reveals predominant compared within multiple tumor types. Our results therefore establish a high dimensional reference map health analyzing disease.

Language: Английский

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Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?

American Society of Clinical Oncology Educational Book, Journal Year: 2019, Volume and Issue: 39, P. 147 - 164

Published: May 1, 2019

The emergence of immune checkpoint blockade therapies over the last decade has transformed cancer treatment in a wide range tumor types. Unprecedented and durable clinical responses difficult-to-treat histologies have been observed. However, despite these promising long-term responses, majority patients fail to respond blockade, demonstrating primary resistance. Additionally, many those who initially eventually experience relapse secondary acquired Both resistance are result complex constantly evolving interactions between cells system. Many mechanisms characterized date, more continue be uncovered. By elucidating targeting resistance, treatments can tailored improve outcomes. This review will discuss landscape response data, different mechanisms, potential therapeutic strategies overcome

Language: Английский

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Spatial Map of Human T Cell Compartmentalization and Maintenance over Decades of Life

Cell, Journal Year: 2014, Volume and Issue: 159(4), P. 814 - 828

Published: Nov. 1, 2014

Mechanisms for human memory T cell differentiation and maintenance have largely been inferred from studies of peripheral blood, though the majority cells are found in lymphoid mucosal sites. We present here a multidimensional, quantitative analysis compartmentalization over six decades life lymphoid, tissues obtained 56 individual organ donors. Our results reveal that distribution tissue residence naive, central, effector memory, terminal subsets is contingent on both their state localization. Moreover, homeostasis driven by cytokine or TCR-mediated signals different CD4+ CD8+ lineages, varies with stage localization, cannot be blood. data provide an unprecedented spatial temporal map maintenance, supporting distinct pathways fate determination homeostasis.

Language: Английский

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T memory stem cells in health and disease

Nature Medicine, Journal Year: 2017, Volume and Issue: 23(1), P. 18 - 27

Published: Jan. 1, 2017

Language: Английский

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Resistance to PD1/PDL1 checkpoint inhibition

Cancer Treatment Reviews, Journal Year: 2016, Volume and Issue: 52, P. 71 - 81

Published: Nov. 27, 2016

Language: Английский

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Epigenetic Modification and Antibody-Dependent Expansion of Memory-like NK Cells in Human Cytomegalovirus-Infected Individuals

Immunity, Journal Year: 2015, Volume and Issue: 42(3), P. 431 - 442

Published: March 1, 2015

Language: Английский

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