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  • 1
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    Online Resource
    Abstract 2945: Depleting hCCR8 mAb Therapy #2: Selection of candidates for the development of innovative depleting anti CCR8 therapeutic antibodies to control the immunosuppressive tumor microenvironment
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2945-2945
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2945-2945
    Abstract: Tumor-infiltrating Tregs (TITR) constitute a sub-family of immuno-suppressive cells abundantly found in multiple solid cancers. They play a critical role in tumor progression and their specific depletion has been recently propose as a novel therapeutic strategy to fight cancers. Based on the transcriptional analysis of tumor infiltrating immune cells, the G-protein coupled receptor CCR8 was found to be expressed on murine and human TITR, but not on proinflammatory effector T cells. The CCR8 receptor therefore represents a unique TITR target for the development of novel depletive antibody-based therapeutics. At Domain Therapeutics, a diverse library of several dozens of mouse mAbs directed against the hCCR8 was discovered and characterized, providing a unique source for the development of a best-in-class and well differentiated anti-hCCR8 depleting antibody for the treatment of cancers.Special attention was paid on two important characteristics for the selection of our depleting mAb candidates: (1) their ability to detect all CCR8 positive immunosuppressive cells and (2) the combination of different killing modes of action (ADCC, ADCP, CDC) to trigger an optimal depletion.Our selected mAb candidates were nominated based on their capacity to bind to immunosuppressive cells present in different tumor tissues and optimal depleting activity. The impact of our mAbs on tumor growth and on the immune tumor microenvironment (TME) were also studied in mouse hCCR8-KI mice. Finally, following a comprehensive in vitro benchmarking mAb analysis, we identified key differentiating points versus competitor’s mAbs. Nominated candidates wil be ready to enter cell line generation efforts in early 2023. Citation Format: Iseulys Richert, Malaury Schappler, Alice Gentil Dit Maurin, Megane Jeannelle, Solene Rose, Pauline Urquia, Dounia Chraa, Luc Baron, Maria Dolores Garcia Fernandez, Quentin Ruet, Camille Dietsch, Orphee Blanchard, Safia Ayachi, Christel Franchet, Alexandre Fontayne, Claudine Vermot-Desroches, Stephan Schann, Nathalie Lenne. Depleting hCCR8 mAb Therapy #2: Selection of candidates for the development of innovative depleting anti CCR8 therapeutic antibodies to control the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14- 19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2945.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2945
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
    Online Resource
    Online Resource
    Image_3.tif
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-9-1)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-9-1)
    Abstract: Glioma is the most common type of primary brain tumor in adults. Patients with the most malignant form have an overall survival time of & lt;16 months. Although considerable progress has been made in defining the adapted therapeutic strategies, measures to counteract tumor escape have not kept pace, due to the developed resistance of malignant glioma. In fact, identifying the nature and role of distinct tumor-infiltrating immune cells in glioma patients would decipher potential mechanisms behind therapy failure. Methods We integrated into our study glioma transcriptomic datasets from the Cancer Genome Atlas (TCGA) cohort (154 GBM and 516 LGG patients). LM22 immune signature was built using CIBERSORT. Hierarchical clustering and UMAP dimensional reduction algorithms were applied to identify clusters among glioma patients either in an unsupervised or supervised way. Furthermore, differential gene expression (DGE) has been performed to unravel the top expressed genes among the identified clusters. Besides, we used the least absolute shrinkage and selection operator (LASSO) and Cox regression algorithm to set up the most valuable prognostic factor. Results Our study revealed, following gene enrichment analysis, the presence of two distinct groups of patients. The first group, defined as cluster 1, was characterized by the presence of immune cells known to exert efficient antitumoral immune response and was associated with better patient survival, whereas the second group, cluster 2, which exhibited a poor survival, was enriched with cells and molecules, known to set an immunosuppressive pro-tumoral microenvironment. Interestingly, we revealed that gene expression signatures were also consistent with each immune cluster function. A strong presence of activated NK cells was revealed in cluster 1. In contrast, potent immunosuppressive components such as regulatory T cells, neutrophils, and M0/M1/M2 macrophages were detected in cluster 2, where, in addition, inhibitory immune checkpoints, such as PD-1, CTLA-4, and TIM-3, were also significantly upregulated. Finally, Cox regression analysis further corroborated that tumor-infiltrating cells from cluster 2 exerted a significant impact on patient prognosis. Conclusion Our work brings to light the tight implication of immune components on glioma patient prognosis. This would contribute to potentially developing better immune-based therapeutic approaches.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.685213
    DOI: 10.3389/fimmu.2021.685213.s001
    DOI: 10.3389/fimmu.2021.685213.s002
    DOI: 10.3389/fimmu.2021.685213.s003
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 3
    Online Resource
    Online Resource
    T lymphocyte subsets in cancer immunity: Friends or foes
    Oxford University Press (OUP) ; 2019
    In:  Journal of Leukocyte Biology Vol. 105, No. 2 ( 2019-01-31), p. 243-255
    Details
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 105, No. 2 ( 2019-01-31), p. 243-255
    Abstract: Although immune-based therapy is proving to be a success in several cancer types, only a set of patients appear to respond to immune checkpoint blockade including PD-1 and CTLA-4. A better understanding of the crucial components of cancer immunity is therefore necessary. T lymphocytes, a key element, are found within the tumor microenvironment and seem to be critical in determining the efficacy of immune surveillance. In this review, we will depict the pro- and antitumor roles of major T cell subsets in distinct cancer tissues. The central role of the mainly antitumor subsets, cytotoxic T cells and Th1 cells, will be delineated. Subsequently, we will indicate how other subsets including Th2, Th17, and T regulatory cells exhibit ambivalent roles. We will also describe the emerging and favorable role of Th9 cells in cancer immunity. In parallel, we will go through main mechanisms by which these cells operate, and will pinpoint pathways, which could be used as potential therapeutic targets in order to positively impact the immune response and ameliorate patients’ clinical outcome. Review on the distinct T cell subsets in cancer immunity and potential T cell-related molecules, which could be targeted in order to improve patients' clinical outcome.
    Type of Medium: Online Resource
    ISSN: 1938-3673 , 0741-5400
    URL: Article
    DOI: 10.1002/JLB.MR0318-097R
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Table_1.docx
    Frontiers Media SA ; 2023
    In:  Frontiers in Immunology Vol. 14 ( 2023-9-11)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 14 ( 2023-9-11)
    Abstract: The crosstalk between the immune system and cancer cells has aroused considerable interest over the past decades. To escape immune surveillance cancer cells evolve various strategies orchestrating tumor microenvironment. The discovery of the inhibitory immune checkpoints was a major breakthrough due to their crucial contribution to immune evasion. The A2AR receptor represents one of the most essential pathways within the TME. It is involved in several processes such as hypoxia, tumor progression, and chemoresistance. However, its clinical and immunological significance in human breast cancer remains elusive. Methods The mRNA expression and protein analysis were performed by RT-qPCR and immunohistochemistry. The log-rank (Mantel-Cox) test was used to estimate Kaplan-Meier analysis for overall survival. Using large-scale microarray data (METABRIC), digital cytometry was conducted to estimate cell abundance. Analysis was performed using RStudio software (7.8 + 2023.03.0) with EPIC, CIBERSORT, and ImmuneCellAI algorithms. Tumor purity, stromal and immune scores were calculated using the ESTIMATE computational method. Finally, analysis of gene set enrichment (GSEA) and the TISCH2 scRNA-seq database were carried out. Results Gene and protein analysis showed that A2AR was overexpressed in breast tumors and was significantly associated with high grade, elevated Ki-67, aggressive molecular and histological subtypes, as well as poor survival. On tumor infiltrating immune cells, A2AR was found to correlate positively with PD-1 and negatively with CTLA-4. On the other hand, our findings disclosed more profuse infiltration of protumoral cells such as M0 and M2 macrophages, Tregs, endothelial and exhausted CD8+ T cells within A2ARhigh tumors. According to the Single-Cell database, A2AR is expressed in malignant, stromal and immune cells. Moreover, it is related to tumor purity, stromal and immune scores. Our results also revealed that CD8+T cells from A2ARhigh patients exhibited an exhausted functional profile. Finally, GSEA analysis highlighted the association of A2AR with biological mechanisms involved in tumor escape and progression. Conclusion The present study is the first to elucidate the clinical and immunological relevance of A2AR in breast cancer patients. In light of these findings, A2AR could be deemed a promising therapeutic target to overcome immune evasion prevailing within the TME of breast cancer patients.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2023.1201632
    DOI: 10.3389/fimmu.2023.1201632.s001
    DOI: 10.3389/fimmu.2023.1201632.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2606827-8
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  • 5
    Online Resource
    Online Resource
    Keratinocyte-derived cytokine TSLP promotes growth and metastasis of melanoma by regulating the tumor-associated immune microenvironment
    American Society for Clinical Investigation ; 2022
    In:  JCI Insight Vol. 7, No. 21 ( 2022-11-8)
    Details
    In: JCI Insight, American Society for Clinical Investigation, Vol. 7, No. 21 ( 2022-11-8)
    Type of Medium: Online Resource
    ISSN: 2379-3708
    URL: Article
    URL: Article
    DOI: 10.1172/jci.insight.161438
    DOI: 10.1172/jci.insight.161438DS1
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2022
    detail.hit.zdb_id: 2874757-4
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