Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors

Human TH17 and regulatory T cells : shared developmental mechanisms and relationship with the intestinal microbiota

Deux populations de lymphocytes T CD4 régulateurs (Treg), les naturels (nTreg) et induits (iTreg), assurent la tolérance au soi et aux microorganismes commensaux et le contrôle des réponses immunitaires exagérées. Au cours de ma thèse j’ai investigué les mécanismes qui permettraient de cibler de façon différentielle une des populations Treg ainsi que le rôle du microbiote intestinal dans l’ontogénie des iTreg. Les iTreg ont des liens avec la population de lymphocytes T CD4 proinflammatoires TH17. Cela m’a amenée à examiner l’expression du gène IL4I1 codant pour une Lphénylalanine oxydase qui inhibe la prolifération des lymphocytes T et exprimé dans les TH17. J’ai montré que parmi les Treg l’IL4I1 était exprimé préférentiellement dans les iTreg et qu’en conditions inflammatoires son expression augmentait et accompagnait la conversion des Treg en TH17. Le profil différentiel d’expression de l’IL4I1 pourrait fournir une base pour le ciblage spécifique des iTreg.Alors que les nTreg se développent dans le thymus, des modèles murins indiquent que le microbiote intestinal joue un rôle important dans l’ontogénie des iTreg et des TH17. Afin d’étudier l’influence du microbiote intestinal sur le développement des iTreg et des TH17 chez l’homme, je me suis intéressée aux bactéries filamenteuses segmentées (SFB) qui jouent un rôle important dans le développement de l’immunité intestinale chez la souris. Nous avons mis en évidence des réponses T CD4 spécifiques de SFB dont une fraction exprimait les facteurs de transcription et les cytokines caractéristiques des Treg et des TH17. De plus, nos données suggèrent que ces réponses pourraient jouer un rôle dans la polyarthrite rhumatoïde.Two populations of regulatory CD4 T cells (Treg), natural Treg (nTreg) and induced Treg (iTreg), ensure tolerance to self and to commensal microorganisms as well as control of exaggerated immune responses. During my PhD research, I investigated mechanisms that could allow for the differential targeting of these Treg populations as well as the role of intestinal microbiota in iTreg ontogeny. iTreg have close ties to TH17, a population of pro-inflammatory CD4 T cells. This led me to examine the expression of the IL4I1 gene, which encodes an L-phenylalanine oxidase able to inhibit T cell proliferation and that is expressed in TH17 cells. We showed that among Treg IL4I1 was preferentially expressed in iTreg and that in inflammatory conditions its expression was enhanced and accompanied Treg conversion into TH17. The differential expression profile of IL4I1 could provide opportunities for the specific targeting of the iTreg population. Whereas nTreg develop in the thymus, data obtained in mouse models indicate that the intestinal microbiota plays a prominent role in the ontogeny of iTreg as well as in the development of TH17. In order to address the influence of the gut microbiota on the development of human iTreg and TH17, I focused on segmented filamentous bacteria (SFB) that play a central role in the development of intestinal immunity in mice. We detected SFB specific CD4 T cell responses in healthy individuals and a fraction of cells expressed Treg and TH17 signature transcription factors and cytokines. In addition, our data suggest that these responses could play a role in rheumatoid arthritis

Circulating Exhausted PD-1+CD39+ Helper CD4 T Cells Are Tumor-Antigen-Specific and Predict Response to PD-1/PD-L1 Axis Blockade

Tumor-infiltrating exhausted PD-1hiCD39+ tumor-antigen (Ag)-specific CD4 T cells contribute to the response to immune checkpoint blockade (ICB), but their circulating counterparts, which could represent accessible biomarkers, have not been assessed. Here, we analyzed circulating PD-1+CD39+ CD4 T cells and show that this population was present at higher proportions in cancer patients than in healthy individuals and was enriched in activated HLA-DR+ and ICOS+ and proliferating KI67+ cells, indicative of their involvement in ongoing immune responses. Among memory CD4 T cells, this population contained the lowest proportions of cells producing effector cytokines, suggesting they were exhausted. In patients with HPV-induced malignancies, the PD-1+CD39+ population contained high proportions of HPV Ag-specific T cells. In patients treated by ICB for HPV-induced tumors, the proportion of circulating PD-1+CD39+ CD4 T cells was predictive of the clinical response. Our results identify CD39 expression as a surrogate marker of circulating helper tumor-Ag-specific CD4 T cells

Microtubule-Driven Stress Granule Dynamics Regulate Inhibitory Immune Checkpoint Expression in T Cells

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PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells

International audienceTumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade

Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage

International audienceIntestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected

Universal Dependencies 2.3

Universal Dependencies is a project that seeks to develop cross-linguistically consistent treebank annotation for many languages, with the goal of facilitating multilingual parser development, cross-lingual learning, and parsing research from a language typology perspective. The annotation scheme is based on (universal) Stanford dependencies (de Marneffe et al., 2006, 2008, 2014), Google universal part-of-speech tags (Petrov et al., 2012), and the Interset interlingua for morphosyntactic tagsets (Zeman, 2008)

Universal Dependencies 2.11

Universal Dependencies is a project that seeks to develop cross-linguistically consistent treebank annotation for many languages, with the goal of facilitating multilingual parser development, cross-lingual learning, and parsing research from a language typology perspective. The annotation scheme is based on (universal) Stanford dependencies (de Marneffe et al., 2006, 2008, 2014), Google universal part-of-speech tags (Petrov et al., 2012), and the Interset interlingua for morphosyntactic tagsets (Zeman, 2008)