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Weulersse Marianne - One of the best experts on this subject based on the ideXlab platform.
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Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy
'Elsevier BV', 2020Co-Authors: Weulersse Marianne, Asrir Assia, Pichler, Andrea C., Lemaitre Lea, Braun Matthias, Carrié Nadège, Joubert Marie-véronique, Le Moine Marie, Do Souto Laura, Gaud GuillaumeAbstract:Through complementary approaches, involving cancer patients’ samples and relevant mouse tumor models, Weulersse et al. reveal that CD8 T cells in the tumor microenvironment lose expression of the activating receptor CD226 (DNAM-1) in a manner that is Eomes dependent. CD226 loss restrains CD8 T cell function and limits the efficacy of cancer immunotherapy.CD8 T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8 T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8 T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226 CD8 T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8 tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in CD226 mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8 T cell function and limits the efficacy of cancer immunotherapy
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Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy
'Elsevier BV', 2020Co-Authors: Weulersse Marianne, Asrir Assia, Pichler, Andrea C., Lemaitre Lea, Braun Matthias, Carrié Nadège, Le Moine Marie, Do Souto Laura, Joubert, Marie Véronique, Gaud GuillaumeAbstract:Through complementary approaches, involving cancer patients’ samples and relevant mouse tumor models, Weulersse et al. reveal that CD8+ T cells in the tumor microenvironment lose expression of the activating receptor CD226 (DNAM-1) in a manner that is Eomes dependent. CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe
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L'absence de CD226 caractérise des LT CD8+ hyporépondeurs au TCR et aux fonctions antitumorales défectueuses
2019Co-Authors: Weulersse MarianneAbstract:Les lymphocytes cytotoxiques T CD8+ (LT CD8+) sont des cellules de l'immunité adaptative qui jouent un rôle majeur dans les réponses immunitaires antitumorales puisqu'ils reconnaissent et tuent spécifiquement les cellules cancéreuses. Cependant, leurs fonctions antitumorales sont souvent limitées par l'expression de récepteurs inhibiteurs tels que CTLA-4 et PD-1. Bien que les immunothérapies basées sur le blocage de ces récepteurs représentent l'une des avancées majeures dans le traitement du cancer, de nombreux cancers y sont réfractaires. Ainsi, il est aujourd'hui nécessaire de comprendre davantage les mécanismes à l'origine de cette résistance thérapeutique et d'identifier d'autres cibles régulant les fonctions antitumorales des LT CD8+. Tandis que les stratégies immunothérapeutiques actuelles se concentrent essentiellement sur l'identification d'autres récepteurs inhibiteurs, le rôle des récepteurs activateurs des LT CD8+ dans la réponse aux immunothérapies reste encore peu approfondi. Initialement décrite comme une molécule d'adhésion, CD226 (DNAM-1) est un récepteur coactivateur exprimé par les cellules NK et les LT CD8+ qui stimule leur production de cytokines inflammatoires et de granules cytolytiques vis-à-vis de cellules cibles suite à son interaction avec ses ligands CD112 et CD155. La nectine CD112 et la "nectine-like" CD155 sont fréquemment exprimées par les cellules tumorales et des modèles murins immunodéficients CD226-/- ont pu démontrer que CD226 joue rôle critique dans l'immunosurveillance antitumorale. Par ailleurs, les récepteurs inhibiteurs TIGIT et CD96 qui rentrent en compétition avec CD226 ont récemment été caractérisés comme des cibles d'immunothérapies intéressantes, ce qui renforce l'idée selon laquelle la réponse immunitaire antitumorale est régulée par CD226. Au cours de ma thèse, j'ai mis en évidence que CD226 identifie les populations LT CD8+ CD226- et LT CD226+ chez des individus sains et des patients atteints de cancer. Des analyses transcriptomiques et fonctionnelles m'ont permis de démontrer que l'absence de CD226 conduit à une altération majeure de la prolifération et des fonctions effectrices des LT CD8+ stimulés par le TCR. Mes analyses effectuées sur des LT CD8+ infiltrant la tumeur chez des patients atteints de cancer et chez des souris porteuses de tumeur m'ont conduit à observer que le développement tumoral favorise l'accumulation des LT CD8+ CD226- hyporépondeurs au TCR au site de la tumeur. Des modèles murins précliniques ont pu ensuite mettre en évidence que cette accumulation progressive des LT CD8+ CD226- dépend du facteur de transcription Eomes. Le phénotype " épuisé " est identique entre les LT CD8+ CD226+ et LT CD226- infiltrant la tumeur et seule l'absence de CD226 est à l'origine de la diminution des fonctions effectrices des LT CD8+ CD226-. De façon importante, j'ai pu observer que l'immunothérapie anti-PD-1 ne parvient pas à restaurer les fonctions des LT CD8+ CD226-, contrairement aux LT CD8+ CD226+. Ainsi, mes résultats indiquent qu'au-delà d'exprimer des récepteurs inhibiteurs, la perte du récepteur coactivateur CD226 est un nouveau mécanisme pouvant contribuer à l'épuisement lymphocytaire et à l'échappement de la tumeur aux LT CD8+. CD226 serait donc un marqueur de bon pronostic pour les patients traités avec les immunothérapies anti-PD-1, et inversement l'absence de CD226 pourrait expliquer en partie les faibles réponses cliniques de certains patients.CD8+ cytotoxic T lymphocytes (CTL) are key immune cells that play an important role in the control of tumor development through their ability of killing cancer cells. However, cancer cells can frequently escape CD8 T-cell recognition and cytolytic functions through the engagement of inhibitory receptors such as CTLA-4 and PD-1. Although immune checkpoint blockade (ICB) such as monoclonal antibody (mAb) anti-PD-1 has represented a promising cancer therapy in cancer care, clinical responses are not observed in the majority of cancer patients. Therefore, elucidating the mechanisms of this lack of responsiveness and finding additional signals that regulate CD8+ T cell anti-tumor functions has become a major priority. While most of the experimental strategy mainly focus on the identification of additional inhibitory receptors, the importance of coactivating receptors in the antitumor CD8+ T cell functions and ICB efficacy remains to be better investigated. Initially described as an adhesion molecule, CD226 (DNAM-1) is co-activating receptor expressed by NK cells and CD8+ T cells that stimulate the secretion of pro-inflammatory cytokines and release of cytolytic granules towards target cells. Its ligands, the nectin and nectin-like receptors CD112 and CD155, are often expressed on cancer cells and CD226 was shown to play a critical role in immunosurveillance in numerous tumor mouse models. The inhibitory receptors TIGIT and CD96 that compete with CD226 were recently identified as promising immunotherapeutic targets to restore CD8+ T cell reactivity against cancer, thus highlighting the importance of CD226 axis in the regulation of anti-tumor immune responses. During my PhD, I found that CD226 identifies CD226- CD8+ and CD226+ CD8+ T cells populations in healthy donors and in cancers patients. Through transcriptomic, molecular and functional analysis, I found that the CD226 absence alters CD8+ T cell responsiveness to TCR stimulation. Unlike CD226+ CD8+ T cells, CD226- CD8+ T cells have deeply intrinsic functional abnormalities such as poor proliferation, cytokines production and cytotoxic functions upon TCR stimulation. Using complementary set of experiments involving human samples and mouse tumors models, I observed that tumor development favors the accumulation of tumor-infiltrating CD226- CD8+ T lymphocytes (TILs) through an Eomes-dependent mechanism. In cancer patients and in preclinical models, the similar exhausted phenotype between CD226- and CD226+ CD8+ TILs suggest that the absence of CD226 identifies highly dysfunctional CD8+ T cells. Importantly, I observed that anti-PD-1 immunotherapy failed to restore effector functions of CD226- CD8+ T cells. Therefore, my results strongly suggest that in addition of expressing inhibitory immune checkpoints, cancer could evade CTL-based mechanisms through the downregulation of CD226. The loss of CD226 could represent a novel mechanism of tumor resistance to ICB and partially explain the functional failures of CD8+ T cells responsible for poor clinical responses in a fraction of cancer patients. Therefore, CD226 could be a predictive marker for the clinical outcomes of ICB-treated cancer patients
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L'absence de CD226 caractérise des LT CD8+ hyporépondeurs au TCR et aux fonctions antitumorales défectueuses
HAL CCSD, 2019Co-Authors: Weulersse MarianneAbstract:CD8+ cytotoxic T lymphocytes (CTL) are key immune cells that play an important role in the control of tumor development through their ability of killing cancer cells. However, cancer cells can frequently escape CD8 T-cell recognition and cytolytic functions through the engagement of inhibitory receptors such as CTLA-4 and PD-1. Although immune checkpoint blockade (ICB) such as monoclonal antibody (mAb) anti-PD-1 has represented a promising cancer therapy in cancer care, clinical responses are not observed in the majority of cancer patients. Therefore, elucidating the mechanisms of this lack of responsiveness and finding additional signals that regulate CD8+ T cell anti-tumor functions has become a major priority. While most of the experimental strategy mainly focus on the identification of additional inhibitory receptors, the importance of coactivating receptors in the antitumor CD8+ T cell functions and ICB efficacy remains to be better investigated. Initially described as an adhesion molecule, CD226 (DNAM-1) is co-activating receptor expressed by NK cells and CD8+ T cells that stimulate the secretion of pro-inflammatory cytokines and release of cytolytic granules towards target cells. Its ligands, the nectin and nectin-like receptors CD112 and CD155, are often expressed on cancer cells and CD226 was shown to play a critical role in immunosurveillance in numerous tumor mouse models. The inhibitory receptors TIGIT and CD96 that compete with CD226 were recently identified as promising immunotherapeutic targets to restore CD8+ T cell reactivity against cancer, thus highlighting the importance of CD226 axis in the regulation of anti-tumor immune responses. During my PhD, I found that CD226 identifies CD226- CD8+ and CD226+ CD8+ T cells populations in healthy donors and in cancers patients. Through transcriptomic, molecular and functional analysis, I found that the CD226 absence alters CD8+ T cell responsiveness to TCR stimulation. Unlike CD226+ CD8+ T cells, CD226- CD8+ T cells have deeply intrinsic functional abnormalities such as poor proliferation, cytokines production and cytotoxic functions upon TCR stimulation. Using complementary set of experiments involving human samples and mouse tumors models, I observed that tumor development favors the accumulation of tumor-infiltrating CD226- CD8+ T lymphocytes (TILs) through an Eomes-dependent mechanism.[...]Les lymphocytes cytotoxiques T CD8+ (LT CD8+) sont des cellules de l'immunité adaptative qui jouent un rôle majeur dans les réponses immunitaires antitumorales puisqu'ils reconnaissent et tuent spécifiquement les cellules cancéreuses. Cependant, leurs fonctions antitumorales sont souvent limitées par l'expression de récepteurs inhibiteurs tels que CTLA-4 et PD-1. Bien que les immunothérapies basées sur le blocage de ces récepteurs représentent l'une des avancées majeures dans le traitement du cancer, de nombreux cancers y sont réfractaires. Ainsi, il est aujourd'hui nécessaire de comprendre davantage les mécanismes à l'origine de cette résistance thérapeutique et d'identifier d'autres cibles régulant les fonctions antitumorales des LT CD8+. Tandis que les stratégies immunothérapeutiques actuelles se concentrent essentiellement sur l'identification d'autres récepteurs inhibiteurs, le rôle des récepteurs activateurs des LT CD8+ dans la réponse aux immunothérapies reste encore peu approfondi. Initialement décrite comme une molécule d'adhésion, CD226 (DNAM-1) est un récepteur coactivateur exprimé par les cellules NK et les LT CD8+ qui stimule leur production de cytokines inflammatoires et de granules cytolytiques vis-à-vis de cellules cibles suite à son interaction avec ses ligands CD112 et CD155. La nectine CD112 et la "nectine-like" CD155 sont fréquemment exprimées par les cellules tumorales et des modèles murins immunodéficients CD226-/- ont pu démontrer que CD226 joue rôle critique dans l'immunosurveillance antitumorale. Par ailleurs, les récepteurs inhibiteurs TIGIT et CD96 qui rentrent en compétition avec CD226 ont récemment été caractérisés comme des cibles d'immunothérapies intéressantes, ce qui renforce l'idée selon laquelle la réponse immunitaire antitumorale est régulée par CD226. Au cours de ma thèse, j'ai mis en évidence que CD226 identifie les populations LT CD8+ CD226- et LT CD226+ chez des individus sains et des patients atteints de cancer. Des analyses transcriptomiques et fonctionnelles m'ont permis de démontrer que l'absence de CD226 conduit à une altération majeure de la prolifération et des fonctions effectrices des LT CD8+ stimulés par le TCR. Mes analyses effectuées sur des LT CD8+ infiltrant la tumeur chez des patients atteints de cancer et chez des souris porteuses de tumeur m'ont conduit à observer que le développement tumoral favorise l'accumulation des LT CD8+ CD226- hyporépondeurs au TCR au site de la tumeur.[...
Gunter Bernhardt - One of the best experts on this subject based on the ideXlab platform.
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cd155 CD226 interaction impacts on the generation of innate cd8 thymocytes by regulating inkt cell differentiation
European Journal of Immunology, 2016Co-Authors: Hristo Georgiev, Akira Shibuya, Inga Ravens, Reinhold Forster, Gunter BernhardtAbstract:The cell surface receptor CD155 influences a variety of immune processes by binding to its ligands CD226, CD96, or TIGIT. Here, we report that the interaction of CD155 with CD226 in the thymus of BALB/c mice has a dual function. It directly influences the dwell time of memory-like CD8(+) T cells, while it is indirectly involved in generating these cells. It was shown earlier that a massive emergence of memory-like CD8 T cells in thymus crucially depends on abundant IL-4, secreted in steady state by iNKT2 (where iNKT is invariant NKT) cells, a subclass of iNKT cells. Here, we show that absence of either CD155 or CD226 in BALB/c mice causes a profound shift in the iNKT subtype composition in thymus, expanding the frequency and numbers of iNKT1 cells at the expense of iNKT2 cells, as well as iNKT17 cells. This shift results in a drop of available IL-4 and creates a scenario similar to that observed in C57BL/6 mice, where iNKT1 cells predominate and iNKT2 cells are much less frequent when compared with BALB/c mice. Yet also in C57BL/6 mice, lack of CD155 or CD226 provokes a further decline in iNKT2 cells, suggesting that the observed effects are not restricted to a particular inbred strain.
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CD226 interaction with cd155 impacts on retention and negative selection of cd8 positive thymocytes as well as t cell differentiation to follicular helper cells in peyer s patches
Immunobiology, 2013Co-Authors: Simon Danisch, Akira Shibuya, Kazuko Shibuya, Sebastian Seth, Quan Qiu, Inga Ravens, Reinhold Forster, Martina Dorsch, Gunter BernhardtAbstract:The immunoglobulin-like glycoprotein CD226 represents a receptor activating cytotoxic T and NK cells taking part in tumour surveillance. In addition, CD226 is involved in the differentiation of naive CD4(+) T cells into effector cells. CD155 that is widely over-expressed on tumour cells, was identified as a counter-receptor of CD226 rendering many cancer cells sensitive to NK driven elimination. However, CD155 was also assigned a role in the establishment of follicular helper T cells in the small intestine and the final maturation of CD8 positive thymocytes. Here we show that mice lacking CD226 are distinguished by virtually identical phenotypes as already reported for CD155 deficient mice: a paucity of follicular helper T cells in Peyer's Patches and of terminally matured CD8 T cells in thymus. Moreover, like CD155, CD226 is involved in negative selection of CD8 thymocytes. These observations establish a firm link between the functions of CD155 and CD226 in several T cell differentiation steps.
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absence of cd155 aggravates acute graft versus host disease
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Sebastian Seth, Inga Ravens, Reinhold Forster, Gunter Bernhardt, Chunwei Lee, Silke Glage, Andre Bleich, Christian KoeneckeAbstract:In a recent paper, Nabekura et al. (1) provided compelling evidence that abrogating DNAM-1 (DNAX accessory molecule-1; CD226) activity resulted in milder development of graft-versus-host disease (GVHD). This is expected, because the role of CD226 as an important costimulatory receptor during T-cell activation is well-documented (2, 3). As shown in the paper (1), CD226 present on donor T cells contributed to the typical syndromes of GVHD. A milder course of GVHD was also achieved by treating transplanted mice with an antibody neutralizing CD226. The authors assumed that CD226 signaling is initiated by interaction of the allogeneic T cells with host cells expressing either CD112 or CD155, the two known ligands of CD226 (1). We analyzed the development of GVHD in mice deficient for CD155. Unexpectedly, the mice succumbed to GVHD within 1 wk, whereas WT mice survived for approximately 3 wk (Fig. 1A). Additional experiments suggested that the observed aggravation in the course of disease is mainly caused by CD4+ donor T cells (Fig. 1A). Additional analyses aimed at identifying the cause of premature death of CD155−/− recipients failed to reveal any differences to WT controls (Fig. 1B). Serum cytokine levels of IFNγ, IL-6, and TNFα as well as the extent of T-cell proliferation were virtually identical when investigated 3 d posttransplantation. We also subjected the intestine of recipients to a detailed histological examination 6 d posttransplantation, but again, significant differences in the degree of injury or infiltrating T cells between WT and CD155−/− mice were not detected. Of note, CD155−/− mice receiving T cell-depleted bone marrow only developed lethal GVHD after T cells differentiated from donor marrow. This corroborated that CD155−/− mice died of deleterious T-cell effects and not because of constitutional defects imposed by CD155 deficiency (Fig. 1A). Fig. 1 (A) After lethal irradiation, WT BALB/c or CD155−/− (Pvrtm1Gbn) BALB/c (KO) mice received 5 × 106 C57BL/6 T cell-depleted bone marrow cells (BM) alone (n = 8) or BM supplemented with 1 × 106 T cells (CD4+ and CD8+ T cells ... Even if the exact cause of the exacerbated course of GVHD in CD155−/− recipients remains elusive, our results suggest that presence of CD155 may attenuate otherwise devastating consequences of GVHD. Because the study by Nabekura et al. (1) clearly showed that CD226-triggered T-cell coactivation contributes to a worsening course of GVHD, CD155 possibly plays a Janus-faced role in GVHD development: its presence exerts protective effects but at the same time, aggravates GVHD by activating donor cells expressing CD226. Alternatively, as already discussed by Nabekura et al. (1), CD112 expressed by host cells in liver and intestine may be largely responsible for the observed CD226 effects. Future studies involving CD112−/− mice will help to clarify this point. Moreover, the GVHD model in use also matters. Whereas Nabekura et al. (1) chose an experimental strategy eliciting GVHD preferentially by CD8+ T cells, our investigations were based on an MHC fully mismatched model where CD4+ T cells mainly contribute to GVHD development (4). Nevertheless, we were unable to prolong survival time of CD155−/− recipients by treating mice with a CD226 neutralizing antibody (Fig. 1A) (5). Despite its importance in CD4+ T-cell stimulation and differentiation (3), CD226 may, thus, not always play a major role in the complex pathophysiology of GVHD.
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heterogeneous expression of the adhesion receptor CD226 on murine nk and t cells and its function in nk mediated killing of immature dendritic cells
Journal of Leukocyte Biology, 2009Co-Authors: Sebastian Seth, Quan Qiu, Inga Ravens, Annamaria Georgoudaki, Benedict J Chambers, Elisabeth Kremmer, Michael K Maier, Niklas Czeloth, Reinhold Foerster, Gunter BernhardtAbstract:The adhesion receptor CD226 (DNAM-1) is a member of the Ig superfamily possessing two extracellular V-like domains. In humans, CD226 was shown to be expressed by NK as well as T cells. During T cell priming, CD226-mediated costimulatory signals may skew the subsequent differentiation into the Th1 pathway. In addition, CD226 expressed on NK and cytotoxic T cells is engaged by its counter-receptor CD155, present on target cells, thereby triggering their elimination. We established mAb specifically recognizing mCD226, demonstrating that CD226 is expressed by precursor and mature but not developing T cells. In contrast, NK cells are distinguished by a rather heterogeneous CD226 expression profile. In addition, expression of CD226 appears coupled to that of other NK cell receptors, as high expression of CD226 was found to correlate with decreased proportions of Ly49D and H positive NK cells. Upon injection into mice, the anti-CD226 antibodies caused selective depletion of CD8 + T cells. Moreover, these antibodies as well as a naturally occurring CD226 splice variant lacking the outermost V-like domain were instrumental in determining that CD226 adheres to CD155 via its first domain. In addition, antibodies were identified as capable of blocking the CD226/ CD155 interaction and to prevent NK-driven killing of immature DC. CD226 is thus the first mNK receptor identified to be essential for the elimination of this particular cell type.
Ricardo Blanco - One of the best experts on this subject based on the ideXlab platform.
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ab0007 the CD226 gene is not involved in giant cell arteritis in the spanish caucasian population
Annals of the Rheumatic Diseases, 2013Co-Authors: Aurora Serrano, Jose A Mirandafilloy, Santos Castaneda, Luis Rodriguezrodriguez, Inmaculada C Morado, R Solans, B Sopena, D Carmona, C Gόmezvaquero, Ricardo BlancoAbstract:Background CD226 genetic variants have been associated with a number of autoimmune diseases. Objectives The aim of this study was to investigate the potential implication of the CD226 loci in the susceptibility to and main clinical manifestations of giant cell arteritis (GCA). Methods A Spanish Caucasian cohort of 455 patients diagnosed with biopsy-proven GCA and 1414 healthy controls were included in the study. Three CD226 polymorphisms, rs727088, rs34794968 and rs763361, were genotyped using the TaqMan® allelic discrimination technology. PLINK software was used for the statistical analyses. Results No significant association between the CD226 polymorphisms and susceptibility to GCA was found (rs727088: P =0.92, OR=1.01 CI 95% 0.86-1.18; rs34794968: P =0.61, OR=1.04 CI 95% 0.89-1.22; rs763361: P =0.88, OR=0.99 CI 95% 0.84-1.16). Similarly, when patients were stratified according to the specific clinical features of GCA such as polymyalgia rheumatica, visual ischemic manifestations or irreversible occlusive disease, no association was observed either between the case subgroups and the control set or between GCA patients with and without the specific features of the disease. Furthermore, the haplotype analysis revealed no significant association with the disease. Conclusions Our results show that the CD226 gene does not play a relevant role in the susceptibility to GCA and clinical manifestations of this vasculitis. References Hafler JP, Maier LM, Cooper JD, Plagnol V, Hinks A, Simmonds MJ, et al. CD226 Gly307Ser association with multiple autoimmune diseases. Genes Immun. 2009; 10:5-10. Lofgren SE, Delgado-Vega AM, Gallant CJ, Sanchez E, Frostegard J, Truedsson L, et al. A 3’-untranslated region variant is associated with impaired expression of CD226 in T and natural killer T cells and is associated with susceptibility to systemic lupus erythematosus. Arthritis Rheum. 2010; 62:3404-3414. Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med. 2002; 347:261-271. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, Miranda-Filloy JA, Gonzalez-Juanatey C, Martin J, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum. 2009; 61:1454-1461. Disclosure of Interest None Declared
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autoimmune disease associated CD226 gene variants are not involved in giant cell arteritis susceptibility in the spanish population
Clinical and Experimental Rheumatology, 2012Co-Authors: Aurora Serrano, F D Carmona, Jose A Mirandafilloy, Santos Castaneda, Luis Rodriguezrodriguez, Inmaculada C Morado, Carmen Gomezvaquero, R Solans, B Sopena, Ricardo BlancoAbstract:Objectives: CD226 genetic variants have been associated with a number of autoimmune diseases. The aim of this study was to investigate the potential implication of the CD226 loci in the susceptibility to and main clinical manifestations of giant cell arteritis (GCA). Methods: A Spanish Caucasian cohort of 455 patients diagnosed with biopsyproven GCA and 1414 healthy controls were included in the study. Three CD226 polymorphisms, rs727088, rs34794968 and rs763361, were genotyped using the TaqMan® allelic discrimination technology. PLINK software was used for the statistical analyses. Results: No significant association between the CD226 polymorphisms and susceptibility to GCA was found (rs727088: p=0.92, OR=1.01, CI 95% 0.86-1.18; rs34794968: p=0.61, OR=1.04, CI 95% 0.89-1.22; rs763361: p=0.88, OR=0.99, CI 95% 0.84-1.16). Similarly, when patients were stratified according to the specific clinical features of GCA such as polymyalgia rheumatica, visual ischaemic manifestations or irreversible occlusive disease, no association was observed either between the case subgroups and the control set or between GCA patients with and without the specific features of the disease. Furthermore, the haplotype analysis revealed no significant association with the clinical manifestations of the disease. Conclusion: Our results show that the three CD226 polymorphisms analysed do not play a relevant role in the susceptibility to GCA and clinical manifestations of this vasculitis. © Clinical and Experimental Rheumatology 2012.
Erxia Shen - One of the best experts on this subject based on the ideXlab platform.
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cd8 t cells expressing both pd 1 and tigit but not CD226 are dysfunctional in acute myeloid leukemia aml patients
Clinical Immunology, 2017Co-Authors: Mengjie Wang, Maohua Zhou, Jessica M Sido, Yu Lin, Guanfang Liu, Qiwen Lin, Jianmei W Leavenworth, Erxia ShenAbstract:Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults with an overall poor prognosis and very limited treatment management. Immune checkpoint blockade of PD-1 alone or combined with other immune checkpoint blockade has gained impressive results in murine AML models by improving anti-leukemia CD8+T cell function, which has greatly promoted the strategy to utilize combined immune checkpoint inhibitors to treat AML patients. However, the expression profiles of these immune checkpoint receptors, such as co-inhibitory receptors PD-1 and TIGIT and co-stimulatory receptor CD226, in T cells from AML patients have not been clearly defined. Here we have defined subsets of CD8+ and CD4+ T cells in the peripheral blood (PB) from newly diagnosed AML patients and healthy controls (HCs). We have observed increased frequencies of PD-1- and TIGIT- expressing CD8+ T cells but decreased occurrence of CD226-expressing CD8+T cells in AML patients. Further analysis of these CD8+ T cells revealed a unique CD8+ T cell subset that expressed PD-1 and TIGIT but displayed lower levels of CD226 was associated with failure to achieve remission after induction chemotherapy and FLT3-ITD mutations which predict poor clinical prognosis in AML patients. Importantly, these PD-1+TIGIT+CD226-CD8+T cells are dysfunctional with lower expression of intracellular IFN-γ and TNF-α than their counterparts in HCs. Therefore, our studies revealed that an increased frequency of a unique CD8+ T cell subset, PD-1+TIGIT+CD226-CD8+T cells, is associated with CD8+T cell dysfunction and poor clinical prognosis of AML patients, which may reveal critical diagnostic or prognostic biomarkers and direct more efficient therapeutic strategies.
Ashmitha Sundarrajan - One of the best experts on this subject based on the ideXlab platform.
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cd155 on tumor cells drives resistance to immunotherapy by inducing the degradation of the activating receptor CD226 in cd8 t cells
Immunity, 2020Co-Authors: Matthias Braun, Amelia Roman Aguilera, Ashmitha Sundarrajan, Dillon Corvino, Kimberley Stannard, Sophie Krumeich, Indrajit Das, Luize G Lima, Lizeth Meza G GuzmanAbstract:The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.
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tumor cd155 drives resistance to immunotherapy by downregulating the activating receptor CD226 in cd8 t cells
2019Co-Authors: Matthias Braun, Amelia Roman Aguilera, Ashmitha Sundarrajan, Dillon Corvino, Indrajit Das, Gabrielle Kelly, Frank Vari, Ailin Lepletier, Sally Pearson, Jason MadoreAbstract:The upregulation of inhibitory molecules is a major driver of immune escape in cancer. In contrast, less is known about the regulation of T cell activating receptors within the tumor microenvironment. Here, we describe that tumor derived CD155, a transmembrane glycoprotein of the immunoglobulin superfamily, downregulates the activating receptor CD226 (DNAM-1) in mouse and human CD8+ T cells, leading to profound loss of effector function and cancer immune evasion. Mechanistically, CD155 drives internalisation of CD226 through phosphorylation of tyrosine 319 (CD226Y319). Accordingly, in T cells a mutation in Y319 led to increased CD226 surface expression improving the efficacy of cancer immunotherapies in mouse models of cancer. In pre-treatment samples from melanoma patients, CD226+ CD8+ T cells significantly correlated with response to immunotherapy and survival. In summary, we discovered a new paradigm in which tumor cells escape destruction by T cells through targeted downregulation of an activating receptor.
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eomes dependent CD226 loss alters tcr responsiveness and restrains cd8 t lymphocyte anti tumor functions
Social Science Research Network, 2019Co-Authors: Marianne Weulersse, Matthias Braun, Indrajit Das, Guillaume Gaud, Assia Asrir, Andrea Charlotte Pichler, Marieveronique Joubert, Laura Do Souto, Clara Maria Scarlata, Ashmitha SundarrajanAbstract:Although anti-PD-1 and anti-CTLA-4 based immune checkpoint blockade (ICB) has represented a turning point in cancer care, clinical responses are observed only in a fraction of cancer patients. Most research focuses on the identification of additional inhibitory receptors restraining the anti-tumor functions of CD8+ T cells. By contrast, herein, we found that loss of the activating receptor CD226 (DNAM-1) was a critical mechanism affecting CD8+ T cell responsiveness to TCR stimulation. Using cancer patients’ samples and preclinical mouse models, we discovered that dysfunctional CD226-negative CD8+ T cells progressively accumulated in the tumor microenvironment through a mechanism involving the T-box transcription factor Eomesodermin (EOMES). More importantly, we demonstrated that CD226-negative tumor infiltrating lymphocytes had reduced anti-tumor functions and failed to respond to ICB. Altogether, our results revealed that CD226 loss is a critical immune escape mechanism restraining CD8+ T cell function and potentially affecting the therapeutic efficacy of cancer immunotherapy.