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Article ; Online: PD-1 regulates ILC3-driven intestinal immunity and homeostasis.

Jacquelot, Nicolas / Xiong, Le / Cao, Wang H J / Huang, Qiutong / Yu, Huiyang / Sayad, Azin / Anttila, Casey J A / Baldwin, Tracey M / Hickey, Peter F / Amann-Zalcenstein, Daniela / Ohashi, Pamela S / Nutt, Stephen L / Belz, Gabrielle T / Seillet, Cyril

Mucosal immunology

2024

Abstract: Interleukin-(IL) 22 production by intestinal group 3 innate lymphoid cells (ILC3) is critical to maintain gut homeostasis. However, IL-22 needs to be tightly controlled; reduced IL-22 expression is associated with intestinal epithelial barrier defect ... ...

Abstract	Interleukin-(IL) 22 production by intestinal group 3 innate lymphoid cells (ILC3) is critical to maintain gut homeostasis. However, IL-22 needs to be tightly controlled; reduced IL-22 expression is associated with intestinal epithelial barrier defect while its overexpression promotes tumor development. Here, using a single-cell ribonucleic acid sequencing approach, we identified a core set of genes associated with increased IL-22 production by ILC3. Among these genes, programmed cell death 1 (PD-1), extensively studied in the context of cancer and chronic infection, was constitutively expressed on a subset of ILC3. These cells, found in the crypt of the small intestine and colon, displayed superior capacity to produce IL-22. PD-1 expression on ILC3 was dependent on the microbiota and was induced during inflammation in response to IL-23 but, conversely, was reduced in the presence of Notch ligand. PD-1
Language	English
Publishing date	2024-03-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2411370-0
ISSN	1935-3456 ; 1933-0219
ISSN (online)	1935-3456
ISSN	1933-0219
DOI	10.1016/j.mucimm.2024.03.002
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Zs.A 6796: Show issues

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Article ; Online: Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.

Chung, Douglas C / Ghaedi, Maryam / Warner, Kathrin / Sayad, Azin / Saibil, Samuel D / Bernardini, Marcus Q / Clarke, Blaise A / Shaw, Patricia A / Butler, Marcus O / Easson, Alexandra / Morrissy, Sorana / Wang, Ben X / Nguyen, Linh / Ohashi, Pamela S / Jacquelot, Nicolas

Oncoimmunology

2024 Volume 13, Issue 1, Page(s) 2349347

Abstract: The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti- ... ...

Abstract	The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46
MeSH term(s)	Humans ; Female ; Ovarian Neoplasms/immunology ; Ovarian Neoplasms/pathology ; Melanoma/immunology ; Melanoma/pathology ; Immunity, Innate ; Carcinoma, Ovarian Epithelial/immunology ; Carcinoma, Ovarian Epithelial/pathology ; Lymphocytes, Tumor-Infiltrating/immunology ; Tumor Microenvironment/immunology ; Lymphocyte Subsets/immunology ; Lymphocyte Subsets/metabolism ; Neoplasms, Glandular and Epithelial/immunology ; Neoplasms, Glandular and Epithelial/pathology ; Programmed Cell Death 1 Receptor/metabolism ; Natural Cytotoxicity Triggering Receptor 1/metabolism ; Dendritic Cells/immunology ; Dendritic Cells/pathology ; Dendritic Cells/metabolism ; Lymphocyte Activation Gene 3 Protein ; Antigens, CD/metabolism
Language	English
Publishing date	2024-05-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-402X
ISSN (online)	2162-402X
ISSN	2162-402X
DOI	10.1080/2162402X.2024.2349347
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Article ; Online: Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy.

Cell reports. Medicine

2024 Volume 5, Issue 3, Page(s) 101465

Abstract: The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector ... ...

Abstract	The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8
MeSH term(s)	Humans ; Animals ; Mice ; CD8-Positive T-Lymphocytes ; Immunotherapy, Adoptive/methods ; Neoplasms/pathology ; Immunotherapy ; Amino Acids
Chemical Substances	Amino Acids
Language	English
Publishing date	2024-03-08
Publishing country	United States
Document type	Journal Article
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2024.101465
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Article ; Online: Identification of acquired Notch3 dependency in metastatic Head and Neck Cancer.

Kondratyev, Maria / Pesic, Aleksandra / Ketela, Troy / Stickle, Natalie / Beswick, Christine / Shalev, Zvi / Marastoni, Stefano / Samadian, Soroush / Dvorkin-Gheva, Anna / Sayad, Azin / Bashkurov, Mikhail / Boasquevisque, Pedro / Datti, Alessandro / Pugh, Trevor J / Virtanen, Carl / Moffat, Jason / Grénman, Reidar A / Koritzinsky, Marianne / Wouters, Bradly G

Communications biology

2023 Volume 6, Issue 1, Page(s) 538

Abstract: During cancer development, tumor cells acquire changes that enable them to invade surrounding tissues and seed metastasis at distant sites. These changes contribute to the aggressiveness of metastatic cancer and interfere with success of therapy. Our ... ...

Abstract	During cancer development, tumor cells acquire changes that enable them to invade surrounding tissues and seed metastasis at distant sites. These changes contribute to the aggressiveness of metastatic cancer and interfere with success of therapy. Our comprehensive analysis of "matched" pairs of HNSCC lines derived from primary tumors and corresponding metastatic sites identified several components of Notch3 signaling that are differentially expressed and/or altered in metastatic lines and confer a dependency on this pathway. These components were also shown to be differentially expressed between early and late stages of tumors in a TMA constructed from over 200 HNSCC patients. Finally, we show that suppression of Notch3 improves survival in mice in both subcutaneous and orthotopic models of metastatic HNSCC. Novel treatments targeting components of this pathway may prove effective in targeting metastatic HNSCC cells alone or in combination with conventional therapies.
MeSH term(s)	Animals ; Mice ; Carcinoma, Squamous Cell ; Head and Neck Neoplasms ; Signal Transduction ; Squamous Cell Carcinoma of Head and Neck ; Humans
Chemical Substances	NOTCH3 protein, human ; Notch3 protein, mouse
Language	English
Publishing date	2023-05-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-04828-9
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Article ; Online: Identification of antigenic epitopes recognized by tumor infiltrating lymphocytes in high grade serous ovarian cancer by multi-omics profiling of the auto-antigen repertoire.

Millar, Douglas G / Yang, S Y Cindy / Sayad, Azin / Zhao, Qingchuan / Nguyen, Linh T / Warner, Kathrin / Sangster, Ami G / Nakatsugawa, Munehide / Murata, Kenji / Wang, Ben X / Shaw, Patricia / Clarke, Blaise / Bernardini, Marcus Q / Pugh, Trevor / Thibault, Pierre / Hirano, Naoto / Perreault, Claude / Ohashi, Pamela S

Cancer immunology, immunotherapy : CII

2023 Volume 72, Issue 7, Page(s) 2375–2392

Abstract: Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, ... ...

Abstract	Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge. To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples. We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8
MeSH term(s)	Male ; Humans ; Female ; Lymphocytes, Tumor-Infiltrating ; Epitopes/metabolism ; CD8-Positive T-Lymphocytes ; Proteomics ; Multiomics ; Antigens, Neoplasm ; Peptides ; Ovarian Neoplasms ; Autoantigens ; Epitopes, T-Lymphocyte
Chemical Substances	Epitopes ; Antigens, Neoplasm ; Peptides ; Autoantigens ; Epitopes, T-Lymphocyte
Language	English
Publishing date	2023-03-21
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-023-03413-7
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Zs.A 1237: Show issues

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Article ; Online: Overproduction of IFNγ by Cbl-b-Deficient CD8+ T Cells Provides Resistance against Regulatory T Cells and Induces Potent Antitumor Immunity.

Han, SeongJun / Liu, Zhe Qi / Chung, Douglas C / Paul, Michael St / Garcia-Batres, Carlos R / Sayad, Azin / Elford, Alisha R / Gold, Matthew J / Grimshaw, Natasha / Ohashi, Pamela S

Cancer immunology research

2022 Volume 10, Issue 4, Page(s) 437–452

Abstract: Regulatory T cells (Treg) are an integral component of the adaptive immune system that negatively affect antitumor immunity. Here, we investigated the role of the E3 ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) in establishing CD8+ T-cell ... ...

Abstract	Regulatory T cells (Treg) are an integral component of the adaptive immune system that negatively affect antitumor immunity. Here, we investigated the role of the E3 ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) in establishing CD8+ T-cell resistance to Treg-mediated suppression to enhance antitumor immunity. Transcriptomic analyses suggested that Cbl-b regulates pathways associated with cytokine signaling and cellular proliferation. We showed that the hypersecretion of IFNγ by Cbl-b-deficient CD8+ T cells selectively attenuated CD8+ T-cell suppression by Tregs. Although IFNγ production by Cbl-b-deficient T cells contributed to phenotypic alterations in Tregs, the cytokine did not attenuate the suppressive function of Tregs. Instead, IFNγ had a profound effect on CD8+ T cells by directly upregulating interferon-stimulated genes and modulating T-cell activation. In murine models of adoptive T-cell therapy, Cbl-b-deficient T cells elicited superior antitumor immune response. Furthermore, Cbl-b-deficient CD8+ T cells were less susceptible to suppression by Tregs in the tumor through the effects of IFNγ. Collectively, this study demonstrates that the hypersecretion of IFNγ serves as a key mechanism by which Cbl-b-deficient CD8+ T cells are rendered resistant to Tregs. See related Spotlight by Wolf and Baier, p. 370.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; CD8-Positive T-Lymphocytes ; Interferon-gamma/metabolism ; Mice ; Proto-Oncogene Proteins c-cbl/genetics ; Proto-Oncogene Proteins c-cbl/metabolism ; T-Lymphocytes, Regulatory
Chemical Substances	Adaptor Proteins, Signal Transducing ; Cblb protein, mouse ; IFNG protein, mouse ; Interferon-gamma (82115-62-6) ; Proto-Oncogene Proteins c-cbl (EC 2.3.2.27)
Language	English
Publishing date	2022-02-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-20-0973
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Zs.A 7022: Show issues

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Article ; Online: Proteomic Dynamics of Breast Cancer Cell Lines Identifies Potential Therapeutic Protein Targets.

Molecular & cellular proteomics : MCP

2023 Volume 22, Issue 8, Page(s) 100602

Abstract: Treatment and relevant targets for breast cancer (BC) remain limited, especially for triple-negative BC (TNBC). We identified 6091 proteins of 76 human BC cell lines using data-independent acquisition (DIA). Integrating our proteomic findings with prior ... ...

Abstract	Treatment and relevant targets for breast cancer (BC) remain limited, especially for triple-negative BC (TNBC). We identified 6091 proteins of 76 human BC cell lines using data-independent acquisition (DIA). Integrating our proteomic findings with prior multi-omics datasets, we found that including proteomics data improved drug sensitivity predictions and provided insights into the mechanisms of action. We subsequently profiled the proteomic changes in nine cell lines (five TNBC and four non-TNBC) treated with EGFR/AKT/mTOR inhibitors. In TNBC, metabolism pathways were dysregulated after EGFR/mTOR inhibitor treatment, while RNA modification and cell cycle pathways were affected by AKT inhibitor. This systematic multi-omics and in-depth analysis of the proteome of BC cells can help prioritize potential therapeutic targets and provide insights into adaptive resistance in TNBC.
MeSH term(s)	Humans ; Signal Transduction ; Proto-Oncogene Proteins c-akt/metabolism ; Proteomics ; Cell Proliferation ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics ; Triple Negative Breast Neoplasms/metabolism ; ErbB Receptors/metabolism
Chemical Substances	Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2023.100602
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Zs.A 5599: Show issues

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Article: B Cells Promote T Cell Immunosenescence and Mammalian Aging Parameters.

bioRxiv : the preprint server for biology

2023

Abstract: A dysregulated adaptive immune system is a key feature of aging, and is associated with age-related chronic diseases and mortality. Most notably, aging is linked to a loss in the diversity of the T cell repertoire and expansion of activated inflammatory ... ...

Abstract	A dysregulated adaptive immune system is a key feature of aging, and is associated with age-related chronic diseases and mortality. Most notably, aging is linked to a loss in the diversity of the T cell repertoire and expansion of activated inflammatory age-related T cell subsets, though the main drivers of these processes are largely unknown. Here, we find that T cell aging is directly influenced by B cells. Using multiple models of B cell manipulation and single-cell omics, we find B cells to be a major cell type that is largely responsible for the age-related reduction of naive T cells, their associated differentiation towards pathogenic immunosenescent T cell subsets, and for the clonal restriction of their T cell receptor (TCR). Accordingly, we find that these pathogenic shifts can be therapeutically targeted via CD20 monoclonal antibody treatment. Mechanistically, we uncover a new role for insulin receptor signaling in influencing age-related B cell pathogenicity that in turn induces T cell dysfunction and a decline in healthspan parameters. These results establish B cells as a pivotal force contributing to age-associated adaptive immune dysfunction and healthspan outcomes, and suggest new modalities to manage aging and related multi-morbidity.
Language	English
Publishing date	2023-09-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.12.556363
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Article ; Online: A Genomically Characterized Collection of High-Grade Serous Ovarian Cancer Xenografts for Preclinical Testing.

Cybulska, Paulina / Stewart, Jocelyn M / Sayad, Azin / Virtanen, Carl / Shaw, Patricia A / Clarke, Blaise / Stickle, Natalie / Bernardini, Marcus Q / Neel, Benjamin G

The American journal of pathology

2018 Volume 188, Issue 5, Page(s) 1120–1131

Abstract: High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignant tumors. Overall survival remains low because of the nearly ubiquitous emergence of platinum resistance and the paucity of effective next- ... ...

Abstract	High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignant tumors. Overall survival remains low because of the nearly ubiquitous emergence of platinum resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for preclinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment. We used gene expression, copy number variation, and exome sequencing analyses to credential HGSC patient-derived xenografts (PDXs) as effective preclinical models that recapitulate the features of human HGSC. Mice bearing PDXs were also treated with standard-of-care carboplatin therapy. PDXs showed similar sensitivity to carboplatin as the patient's tumor at the time of sampling. PDXs also recapitulated the diversity of genomic alterations (copy number variation and mutation profiles) previously described in large data sets that profiled HGSC. Furthermore, mRNA profiling showed that the PDXs represent all HGSC subtypes with the exception of the immunoreactive group. Credentialing of PDX models of HGSC should aid progress in HGSC research by providing improved preclinical models of HGSC that can be used to test novel targets and more accurately evaluate their likelihood of success.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Cystadenocarcinoma, Serous/genetics ; Cystadenocarcinoma, Serous/pathology ; DNA Copy Number Variations ; Female ; Haplotypes ; Heterografts ; Humans ; Middle Aged ; Mutation ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology
Language	English
Publishing date	2018-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2018.01.019
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Article ; Online: Computational modeling of ovarian cancer dynamics suggests optimal strategies for therapy and screening.

Gu, Shengqing / Lheureux, Stephanie / Sayad, Azin / Cybulska, Paulina / Hogen, Liat / Vyarvelska, Iryna / Tu, Dongsheng / Parulekar, Wendy R / Nankivell, Matthew / Kehoe, Sean / Chi, Dennis S / Levine, Douglas A / Bernardini, Marcus Q / Rosen, Barry / Oza, Amit / Brown, Myles / Neel, Benjamin G

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 25

Abstract: High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Treatment is not uniform, with some patients undergoing primary debulking surgery followed by chemotherapy (PDS) and others being treated directly with chemotherapy ...

Abstract	High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Treatment is not uniform, with some patients undergoing primary debulking surgery followed by chemotherapy (PDS) and others being treated directly with chemotherapy and only having surgery after three to four cycles (NACT). Which strategy is optimal remains controversial. We developed a mathematical framework that simulates hierarchical or stochastic models of tumor initiation and reproduces the clinical course of HGSC. After estimating parameter values, we infer that most patients harbor chemoresistant HGSC cells at diagnosis and that, if the tumor burden is not too large and complete debulking can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. These predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management.
MeSH term(s)	Aged ; Cohort Studies ; Computer Simulation ; Cystadenocarcinoma, Serous/diagnosis ; Cystadenocarcinoma, Serous/pathology ; Cystadenocarcinoma, Serous/therapy ; Cytoreduction Surgical Procedures ; Early Detection of Cancer ; Female ; Humans ; Middle Aged ; Models, Biological ; Neoadjuvant Therapy ; Neoplasm Grading ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/pathology ; Ovarian Neoplasms/surgery ; Ovarian Neoplasms/therapy ; Survival Analysis ; Treatment Outcome ; Tumor Burden
Language	English
Publishing date	2021-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2026663118
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