Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors

To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL

Tumor-Associated Tertiary Lymphoid Structures: A Cancer Biomarker and a Target for Next-generation Immunotherapy

International audienceThe different forms of lymphoid organization that coexist in our bodies appeared at distinct time points during the evolution of the animal kingdom. Some of these forms are constitutive, either in fully dedicated organs, such as lymph nodes, or in tissue interfacing with the external environment, such as mucosal-associated lymphoid tissues. Others, known as tertiary lymphoid structures (TLS), are selectively induced in response to inflammation in any peripheral tissues and organs. In this chapter, we discuss the functional interest of each of these lymphoid organizations under different physiopathological conditions. In the context of cancer, recent findings have identified TLS formation as a hallmark of active T- and B-cell immune responses against tumors. TLS are thus a powerful prognostic factor in nearly all solid cancers, which must be taken into account along with the tumor microenvironment. The presence of TLS also predicts the response to immunotherapy including immune checkpoint blockade. With tumor-associated TLS now a key target for the next generation of immunotherapy, this chapter discusses their potential therapeutic manipulations in oncology

Key Features of Gamma-Delta T-Cell Subsets in Human Diseases and Their Immunotherapeutic Implications

The unique features of gamma-delta (γδ) T cells, related to their antigen recognition capacity, their tissue tropism, and their cytotoxic function, make these cells ideal candidates that could be targeted to induce durable immunity in the context of different pathologies. In this review, we focus on the main characteristics of human γδ T-cell subsets in diseases and the key mechanisms that could be explored to target these cells

La biologie des cibles PD-1 et CTLA-4 et la question des biomarqueurs

International audienceThe 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.L’identification dans les années 1990 du rôle des molécules CTLA-41 et PD-1, des récepteurs inhibiteurs des lymphocytes T (LT), dans le contrôle de la réponse immunitaire anti-tumorale, a conduit à l’attribution du Prix Nobel de Physiologie ou Médecine en 2018 à James Allison et Tasuku Honjo. Ces récepteurs inhibiteurs définissent ainsi des points de contrôle immunologique, communément nommés par l’anglicisme immune checkpoints, indispensables pour éviter un retentissement délétère de la réponse immunitaire sur les tissus sains et ainsi garantir l’intégrité de l’hôte. Cette découverte majeure a conduit Allison et Honjo à développer des anticorps capables de provoquer le relâchement de ces « freins » immunitaires, permettant ainsi d’attaquer avec efficacité les cellules tumorales. La molécule CTLA-4 module l’amplitude de l’activation précoce des LT et inhibe l’activité de CD28, un co-récepteur activateur majeur de ces cellules. La molécule PD-1 est, elle, exprimée par les LT mémoires et effecteurs, et semble intervenir dans la régulation des cellules chroniquement activées, comme lors des processus inflammatoires. Les traitements par anticorps qui découlent de ces découvertes ont pris une place majeure dans l’arsenal des thérapies anti-cancéreuses. Cette revue présente une synthèse des connaissances sur CTLA-4, PD-1 et leurs ligands, de leurs mécanismes d’action et de régulation, ainsi qu’un état des lieux de la compréhension des biomarqueurs associés à la réponse clinique des traitements par anticorps anti-PD-1/PD-L1 et anti-CTLA-4

Rôle des structures lymphoïdes tertiaires dans le recrutement et l'activation des lymphocytes T et valeur pronostique associée dans le cancer pulmonaire humain

Le rôle majeur du système immunitaire dans le contrôle des tumeurs est aujourd hui clairement établi et l impact pronostique favorable des lymphocytes T (LT) intratumoraux a été démontré dans la majorité des cancers humains. Néanmoins, les mécanismes gouvernant leur recrutement et leur activation au sein des tumeurs demeurent mal compris. Le paradigme actuel veut que la réponse immunitaire anti-tumorale soit initiée à distance de la tumeur, dans les organes lymphoïdes secondaires (SLO). Au sein des tumeurs pulmonaires humaines, nous avons rapporté la présence de structures lymphoïdes tertiaires (TLS) présentant de fortes analogies structurales avec les SLO. Nous avons émis l hypothèse que les TLS pourraient jouer un rôle majeur dans l établissement d une immunité protectrice. Nous avons mis en évidence, spécifiquement au sein des TLS, une expression coordonnée de chimiokines et de molécules d adhérence associée à la présence de LT et de vaisseaux sanguins spécialisés dans leur recrutement. J ai ensuite démontré que la densité de TLS était associée à une signature immunitaire intratumorale particulière caractérisée par une infiltration massive de LT CD8+ et une expression coordonnée des gènes de l immunité à médiation cellulaire (polarisation Th1, cytotoxicité, activation des LT). J ai enfin rapporté qu une forte infiltration de LT CD8+ était corrélée à un pronostic de survie favorable, ceci uniquement lorsqu elle est associée à la présence de TLS. L ensemble de ces données suggère que les TLS peuvent participer activement à la formation du contexte immunitaire intratumoral et promouvoir l'établissement d'une immunité anti-tumorale protectriceThe major role of the immune system against tumor development is now clearly established. A favorable prognostic impact of T cell infiltrate has been demonstrated in the majority of human cancers. Nevertheless, the mechanisms governing T cell recruitment and activation into tumors remain poorly characterized. A dogma is that anti-tumor immune response takes place at distance of the tumor, in secondary lymphoid organs (SLO). We previously reported the presence of tertiary lymphoid structures (TLS) in human lung tumors. Based on their structural analogy with SLO, we hypothesized that these TLS could be implicated in the shaping of a protective anti-tumor immune response. A specific chemoattractants gene expression signature associated with the presence of high endothelial venules and T cells was identified in these TLS. We demonstrated that TLS density predicts a strong infiltration of CD8+ T cells associated with a coordinated expression of cell-mediated immune response related genes (Th1 polarization, cytotoxicity, T cell activation) in lung tumors. Finally, we observed that CD8+ T cell density is associated with a favorable outcome only in tumors with a high density of TLS. All together, these data strongly argue for an active participation of TLS in shaping the immune contexture for the establishment of a protective anti-tumor immune responsePARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Quel avenir pour les lymphocytes B infiltrant les tumeurs solides

Le rôle des lymphocytes B (LB) dans l’immuno-surveillance des tumeurs a longtemps été négligé car il a été souvent considéré comme peu efficace, voire pro-tumoral. Des études approfondies du microenvironnement immunitaire, notamment dans les cancers humains, ont permis de préciser la nature des interactions entre le LB et ses partenaires cellulaires. Cette revue examine un certain nombre de paramètres qui dictent le devenir du LB vers une fonction pro-ou anti-tumorale. Ainsi, la capacité à élaborer une immunité antitumorale qui repose sur les lymphocytes B, et/ ou des anticorps qu’ils sécrètent, fait appel à une palette très variée de mécanismes moléculaires et cellulaires dont certains pourraient représenter de nouvelles cibles thérapeutiques en oncologie

Tertiary Lymphoid Structures: An Anti-tumor School for Adaptive Immune Cells and an Antibody Factory to Fight Cancer?

International audienceTertiary lymphoid structures (TLS) present in human solid tumors are essential for the shaping of a favorable immune micro-environment to control tumor development in most cases. They represent a formidable school for T-cell priming, B cell activation, and differentiation into plasma cells and an exquisitely located factory for antibody production. The manipulation of TLS neogenesis and maintenance represents, therefore, an exciting task to set up efficient anti-cancer vaccine strategies leading to long-lasting anti-tumor adaptive responses. To achieve this goal, a number of important issues are still pending. How TLS-T and-B cells and antibodies locally produced are related to the improved survival of cancer patients with high density of TLS is still unclear. In addition, the mechanisms by which tumors escape the immune surveillance exerted by TLS are still poorly understood and the role of immune suppressive cytokines, regulatory T cells, and/or antibodies in this process remains to be explored. The identification of the key parameters that distinguish TLS with anti-or possible pro-tumor activity is also essential to make the therapeutic targeting of TLS a success. Finally, how TLS-based therapeutic approaches can be associated with targeted therapies or immunointerventions, such as the use of ICP blockers to improve anti-tumor responses, is an open question. We will discuss these different issues in the present review

Harnessing the power of oncolytic virotherapy and tertiary lymphoid structures to amplify antitumor immune responses in cancer patients

International audienceTertiary lymphoid structures (TLS) are ectopic aggregates of immune cells that develop in non-lymphoid tissues under persistent inflammation. Since their presence has been associated with a better prognosis in cancer patients, modulating TLS formation is being part of new challenges in immunotherapy. Although mechanisms underlying TLS genesis are still not fully understood, different strategies have been developed in preclinical models to induce their formation and ultimately enhance antitumor responses. Herein, we will discuss a new approach that would consist in using oncolytic viruses (OV). These viruses have the unique feature to preferentially infect, replicate in and kill cancer cells. Their immunoadjuvant property, their use as a vector of therapeutic molecules and their selectivity for cancer cells, make them an attractive strategy to induce TLS in the tumor microenvironment. This review will examine the current knowledge about TLS neogenesis, approaches for inducing them, and relevance of using OV for this purpose, especially in combination with immunotherapy such as immune checkpoint blockade

Repenser la place des lymphocytes B et des structures lymphoïdes tertiaires dans l’immunothérapie des cancers

International audienc