Abstract
The identification in the 1990's of the role of CTLA-4 and PD-1, two inhibitory receptors of T lymphocytes, in the control of the anti-tumor immune responses, led to the awarding of the Nobel Prize in Physiology or Medicine in 2018 to Dr. James Allison and Dr. Tasuku Honjo. These inhibitory receptors called immune checkpoints are essential to prevent any deleterious impact of on-going immune responses against pathogens or cancer cells on healthy tissues and, hence, guarantee the integrity of the host. These major discoveries have led James Allison and Tasuku Honjo to develop anti-CTLA-4 and anti-PD1/L-1 antibodies, respectively, in order to switch off these immune "brakes", making it possible to efficiently attack tumor cells. CTLA-4 regulates the amplitude of the early T-cell activation and inhibits the activity of CD28, a major activating co-receptor expressed by T cells. PD-1 is expressed by memory and effector T lymphocytes and is involved in the regulation of chronically activated cells, as observed during inflammatory processes. Immunotherapeutic treatments resulting from these discoveries have now a major place in the arsenal of anti-cancer therapies. This review presents firstly a synthesis of knowledge on CTLA-4, PD-1 and their ligands, their mechanisms of action and regulation and, secondly, an overview of biomarkers that have been associated with clinical response to anti-PD-1/PD-L1 and anti-CTLA-4 antibody therapies.
Highlights
This review presents firstly a synthesis of knowledge on CTLA-4, PD-1 and their ligands, their mechanisms of action and regulation and, secondly, an overview of biomarkers that have been associated with clinical response to anti-PD-1/PD-L1 and anti-CTLA-4 antibody therapies. ‡
Costantini A, Julie C, Dumenil C, et al Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab
Summary
Un des enjeux majeurs des stratégies ciblant les points de contrôle immunitaire (en anglais immune checkpoint, ou ICP) est de restaurer les fonctions cytotoxiques des cellules effectrices, fonctions intimement liées à leur état d’activation. Alors que de nombreuses cellules de l’immunité adaptative et innée participent au développement des réponses anti-tumorales, un grand intérêt est actuellement porté à l’activité cytolytique des LT CD8+. L’axe TCR/complexe CMH-peptide L’activation complète du LT implique en premier lieu la reconnaissance par son TCR (T-cell receptor) du complexe constitué d’une molécule du complexe majeur d’histocompatibilité (CMH) de classe I ou II et d’un peptide antigénique, présenté par les cellules présentatrices d’antigènes (CPA). Les molécules « accessoires », CD28, à la surface des LT, et ses deux ligands CD80 et CD86, à la surface des CPA, vont ensuite être engagées au niveau de la synapse immunologique pour conduire à l’activation complète du LT. Cette cascade d’évènements va permettre la sécrétion d’IL(interleukine)-2 et accroître la survie du LT en le préservant, dans un premier
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