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Article ; Online: Understanding the Role of T-Cells in the Antimyeloma Effect of Immunomodulatory Drugs.

D'Souza, Criselle / Prince, H Miles / Neeson, Paul J

2021 Volume 12, Page(s) 632399

Abstract: Immunomodulatory drugs (IMiDs) are effective treatments for patients with multiple myeloma. IMiDs have pleotropic effects including targeting the myeloma cells directly, and improving the anti-myeloma immune response. In the absence of myeloma cells, ... ...

Abstract	Immunomodulatory drugs (IMiDs) are effective treatments for patients with multiple myeloma. IMiDs have pleotropic effects including targeting the myeloma cells directly, and improving the anti-myeloma immune response. In the absence of myeloma cells, lenalidomide and pomalidomide induce CD4
MeSH term(s)	Drug Resistance, Neoplasm ; Drug Therapy, Combination ; Humans ; Immunologic Factors/pharmacology ; Immunologic Factors/therapeutic use ; Immunotherapy ; Killer Cells, Natural/drug effects ; Killer Cells, Natural/immunology ; Multiple Myeloma/drug therapy ; Multiple Myeloma/immunology ; Plasma Cells/drug effects ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; Tumor Microenvironment/drug effects
Chemical Substances	Immunologic Factors
Language	English
Publishing date	2021-03-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.632399
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Article ; Online: Combining chemotherapy with CAR-T cell therapy in treating solid tumors.

Wang, Arthur Xuan / Ong, Xiao Jing / D'Souza, Criselle / Neeson, Paul J / Zhu, Joe Jiang

Frontiers in immunology

2023 Volume 14, Page(s) 1140541

Abstract: Chemotherapy has long been a standard treatment for a wide range of malignancies, where patients typically undergo multiple rounds of chemotherapy regimens to control tumor growth. In the clinic, the chemotherapy drugs cyclophosphamide and fludarabine ... ...

Abstract	Chemotherapy has long been a standard treatment for a wide range of malignancies, where patients typically undergo multiple rounds of chemotherapy regimens to control tumor growth. In the clinic, the chemotherapy drugs cyclophosphamide and fludarabine are commonly used prior to Chimeric Antigen Receptor T (CAR-T) cell therapy to lymphodeplete and improve CAR-T cell engraftment. In this review, we discuss the use of chemotherapy in combination with CAR-T cell therapy. We also show that chemotherapy can deplete immunosuppressive cells, promote a pro-inflammatory tumor microenvironment, disrupt tumor stroma, and improve CAR-T cell recruitment to the tumor. Although the combination of chemotherapy plus CAR-T cell therapy is promising, certain aspects of chemotherapy also pose a challenge. In addition, the combined therapeutic effect may be heavily dependent on the dose and the treatment schedule. Thus, we also discussed the obstacles to effective clinical outcomes of the combination therapy.
MeSH term(s)	Humans ; Receptors, Chimeric Antigen ; Neoplasms/therapy ; Immunotherapy, Adoptive ; T-Lymphocytes ; Cell- and Tissue-Based Therapy ; Tumor Microenvironment
Chemical Substances	Receptors, Chimeric Antigen
Language	English
Publishing date	2023-03-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1140541
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Article ; Online: CAR-T Plus Radiotherapy: A Promising Combination for Immunosuppressive Tumors.

Qin, Vicky Mengfei / Haynes, Nicole M / D'Souza, Criselle / Neeson, Paul J / Zhu, Joe Jiang

Frontiers in immunology

2022 Volume 12, Page(s) 813832

Abstract: Radiotherapy (RT) is the standard-of-care treatment for more than half of cancer patients with localized tumors and is also used as palliative care to facilitate symptom relief in metastatic cancers. In addition, RT can alter the immunosuppressive tumor ... ...

Abstract	Radiotherapy (RT) is the standard-of-care treatment for more than half of cancer patients with localized tumors and is also used as palliative care to facilitate symptom relief in metastatic cancers. In addition, RT can alter the immunosuppressive tumor microenvironment (TME) of solid tumors to augment the anti-tumor immune response of immune checkpoint blockade (ICB). The rationale of this combination therapy can also be extended to other forms of immunotherapy, such as chimeric antigen receptor T cell (CAR-T) therapy. Similar to ICB, the efficacy of CAR-T therapy is also significantly impacted by the immunosuppressive TME, leading to compromised T cell function and/or insufficient T cell infiltration. In this review, we will discuss some of the key barriers to the activity of CAR-T cells in the immunosuppressive TME and focus on how RT can be used to eliminate or bypass these barriers. We will present the challenges to achieving success with this therapeutic partnership. Looking forward, we will also provide strategies currently being investigated to ensure the success of this combination strategy in the clinic.
MeSH term(s)	Combined Modality Therapy ; Disease Management ; Humans ; Immunosuppression Therapy/methods ; Immunotherapy, Adoptive/adverse effects ; Immunotherapy, Adoptive/methods ; Neoplasms/diagnosis ; Neoplasms/etiology ; Neoplasms/mortality ; Neoplasms/therapy ; Prognosis ; Radiotherapy/adverse effects ; Radiotherapy/methods ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Treatment Outcome
Chemical Substances	Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen
Language	English
Publishing date	2022-01-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.813832
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Article: Chimeric Antigen Receptor beyond CAR-T Cells.

Qin, Vicky Mengfei / D'Souza, Criselle / Neeson, Paul J / Zhu, Joe Jiang

Cancers

2021 Volume 13, Issue 3

Abstract: Chimeric antigen receptors (CAR) are genetically engineered receptors that can recognise specific antigens and subsequently activate downstream signalling. Human T cells engineered to express a CAR, also known as CAR-T cells, can target a specific tumour ...

Abstract	Chimeric antigen receptors (CAR) are genetically engineered receptors that can recognise specific antigens and subsequently activate downstream signalling. Human T cells engineered to express a CAR, also known as CAR-T cells, can target a specific tumour antigen on the cell surface to mediate a cytotoxic response against the tumour. CAR-T cell therapy has achieved remarkable success in treating hematologic malignancies, but not in solid tumours. Currently, extensive research is being carried out to make CAR-T cells a therapy for solid tumours. To date, most of the research interest in the field has focused on cytotoxic T lymphocytes as the carrier of CAR products. However, in addition to T cells, the CAR design can be introduced in other immune cells, such as natural killer (NK)/NKT cells, γδ T cells, mucosal-associated invariant T (MAIT) cells, dendritic cells (DC), macrophages, regulatory T cells (Treg), B cells, etc. Some of the CAR-engineered immune cells, such as CAR- γδ T and CAR-NK/NK-T cells, are directly involved in the anti-tumour response, demonstrated in preclinical studies and/or clinical trials. CAR-Tregs showed promising therapeutic potential in treating autoimmune diseases. In particular, B cells engineered with chimeric receptors can be used as a platform for long-term delivery of therapeutic proteins, such as recombinant antibodies or protein replacement, in an antigen-specific manner. CAR technology is one of the most powerful engineering platforms in immunotherapy, especially for the treatment of cancers. In this review, we will discuss the recent application of the CAR design in non-CAR-T cells and future opportunities in immunotherapy.
Language	English
Publishing date	2021-01-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13030404
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Article ; Online: Single-Cell Gene Expression, Clonality, and Feature Barcoding of Melanoma Tumor-Infiltrating Lymphocytes.

Pizzolla, Angela / Keam, Simon P / D'Souza, Criselle / Semple, Timothy / Neeson, Paul J

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2265, Page(s) 529–541

Abstract: We describe here a protocol to measure gene expression, T cell receptor (TCR) sequence, and protein expression by single T cells extracted from melanoma, using 10× Chromium technology. This method includes freezing and thawing of the melanoma ... ...

Abstract	We describe here a protocol to measure gene expression, T cell receptor (TCR) sequence, and protein expression by single T cells extracted from melanoma, using 10× Chromium technology. This method includes freezing and thawing of the melanoma infiltrating lymphocytes, staining of cells with fluorescent and barcode-conjugated antibodies, sorting of T cells, and loading the cells on the 10× Chromium Controller. After sequencing, analysis includes quality control, genetic demultiplexing to resolve genetically different samples, and T cell clonality and clustering analysis. Single cell RNA sequencing paints the complete portrait of individual T cells, including their clonality and phenotype, and it reconstructs a complete picture of the T cell infiltrate in a tumor that is represented as cell clustering similar to a pointillism painting.
MeSH term(s)	Humans ; Lymphocytes, Tumor-Infiltrating/immunology ; Melanoma/genetics ; Melanoma/immunology ; RNA-Seq ; Receptors, Antigen, T-Cell/immunology ; Single-Cell Analysis
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2021-03-11
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1205-7_37
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Article ; Online: Revealing the protective and pathogenic potential of MAIT cells.

D'Souza, Criselle / Chen, Zhenjun / Corbett, Alexandra J

Molecular immunology

2018 Volume 103, Page(s) 46–54

Abstract: Mucosal-associated Invariant T (MAIT) cells represent a large proportion of T cells in human blood, and are also present throughout the body, being concentrated at mucosal sites. Their high level of conservation throughout mammalian evolution and ... ...

Abstract	Mucosal-associated Invariant T (MAIT) cells represent a large proportion of T cells in human blood, and are also present throughout the body, being concentrated at mucosal sites. Their high level of conservation throughout mammalian evolution and recognition of conserved microbial antigens, derived from precursors of riboflavin (vitamin B2) biosynthesis, suggest an important role in protective immunity to pathogens. However, the picture that is emerging of MAIT cell immune function is increasingly complex, with numerous correlations of MAIT cell numbers with human diseases, and with recent studies demonstrating their pathogenic potential. The conditions that drive MAIT cell responses towards a protective versus pathogenic role are only beginning to be deciphered and, yet, must be understood for any attempt to harness MAIT cells therapeutically. In this review we summarise our current knowledge of immune protection and pathology driven by MAIT cells, models used to study their role in immunity and steps towards elucidating the immune signals driving these responses.
MeSH term(s)	Adaptive Immunity/immunology ; Animals ; Antigen Presentation/immunology ; Antigens, Bacterial/immunology ; Helicobacter pylori/immunology ; Helicobacter pylori/physiology ; Humans ; Immunity/immunology ; Immunity, Mucosal/immunology ; Mucosal-Associated Invariant T Cells/immunology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/microbiology
Chemical Substances	Antigens, Bacterial
Language	English
Publishing date	2018-09-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2018.08.022
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Article ; Online: Aberrant DNA methylation at Igf2-H19 imprinting control region in spermatozoa upon neonatal exposure to bisphenol A and its association with post implantation loss.

Doshi, Tanvi / D'souza, Criselle / Vanage, Geeta

Molecular biology reports

2013 Volume 40, Issue 8, Page(s) 4747–4757

Abstract: Bisphenol A (BPA) is an estrogenic compound commonly used in manufacture of various consumer products. Earlier studies from our group have demonstrated that neonatal exposure of male rats to BPA causes decrease in sperm count and motility, increase in ... ...

Abstract	Bisphenol A (BPA) is an estrogenic compound commonly used in manufacture of various consumer products. Earlier studies from our group have demonstrated that neonatal exposure of male rats to BPA causes decrease in sperm count and motility, increase in post implantation loss, ultimately leading to subfertility during adulthood. One of the factors contributing for post implantation loss is altered methylation pattern of imprinted genes. The present study was undertaken to investigate the molecular effects of neonatal exposure of male rats to BPA (2.4 μg/pup) (F0) on the methylation of H19 imprinting control region (ICR) in resorbed embryo (F1) and compared with spermatozoa of their respective sires (F0). We observed a significant down regulation in the transcript expression of Igf2 and H19 genes in BPA resorbed embryo (F1) as compared to control viable embryo. A significant hypomethylation was observed at the H19 ICR in the spermatozoa as well as in resorbed embryo sired by rats exposed neonatally to BPA. These results indicated that the aberrant methylation at ICR in spermatozoa was inherited by embryo which causes perturbation in the expression of Igf2 and H19, ultimately leading to post implantation loss. This could be one of the possible mechanisms of BPA induced adverse epigenetic effects on male fertility.
MeSH term(s)	Animals ; Animals, Newborn ; Base Sequence ; Benzhydryl Compounds/administration & dosage ; Benzhydryl Compounds/toxicity ; Cloning, Molecular ; DNA Methylation/drug effects ; DNA Primers/genetics ; DNA, Complementary/biosynthesis ; Embryo Loss/chemically induced ; Gene Expression Regulation, Developmental/drug effects ; Injections, Subcutaneous ; Insulin-Like Growth Factor II/metabolism ; Male ; Molecular Sequence Data ; Phenols/administration & dosage ; Phenols/toxicity ; RNA, Long Noncoding/metabolism ; Rats ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Spermatozoa/drug effects
Chemical Substances	Benzhydryl Compounds ; DNA Primers ; DNA, Complementary ; H19 long non-coding RNA ; Phenols ; RNA, Long Noncoding ; Insulin-Like Growth Factor II (67763-97-7) ; bisphenol A (MLT3645I99)
Language	English
Publishing date	2013-05-08
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186544-4
ISSN	1573-4978 ; 0301-4851
ISSN (online)	1573-4978
ISSN	0301-4851
DOI	10.1007/s11033-013-2571-x
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Zs.A 1140: Show issues

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Article ; Online: Using Mass Cytometry to Analyze the Tumor-Infiltrating Lymphocytes in Human Melanoma.

Tantalo, Daniela / Nguyen, Thu / Yeang, Han Xian Aw / Zhu, Joe / Macdonald, Sean / Wang, Minyu / de Silva, Harini / D'Souza, Criselle / Pizzolla, Angela / Neeson, Paul J

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2265, Page(s) 543–555

Abstract: Here we describe the application of mass cytometry to analyze tumor-infiltrating lymphocytes in human melanoma. Mass cytometry is the coupling of flow cytometry and mass spectrometry, which allows for the simultaneous measurement of 40+ cell parameters ... ...

Abstract	Here we describe the application of mass cytometry to analyze tumor-infiltrating lymphocytes in human melanoma. Mass cytometry is the coupling of flow cytometry and mass spectrometry, which allows for the simultaneous measurement of 40+ cell parameters on a per cell basis. Heavy metal-labeled antibodies can bind to proteins (CD markers, transcription factors, cytokines) on the cell surface and in the cytoplasm/nucleus. As labeled cells pass through the CyTOF, the instrument detects the heavy metals. Combining these signals allows description of melanoma tumor-infiltrating lymphocytes at a greater depth than alternative phenotyping strategies and enables detailed analyses of a variety of cellular parameters, including immune cell lineage, activation status, and functional polarization.
MeSH term(s)	Flow Cytometry ; Humans ; Lymphocytes, Tumor-Infiltrating/metabolism ; Lymphocytes, Tumor-Infiltrating/pathology ; Mass Spectrometry ; Melanoma/metabolism ; Melanoma/pathology ; Single-Cell Analysis
Language	English
Publishing date	2021-03-11
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1205-7_38
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Article ; Online: PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia

Li, Jessica / Whelan, Sarah / Kotturi, Maya F / Meyran, Deborah / D'Souza, Criselle / Hansen, Kyle / Liang, Spencer / Hunter, John / Trapani, Joseph A / Neeson, Paul J

Haematologica

2021 Volume 106, Issue 12, Page(s) 3115–3124

Abstract: This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, ...

Abstract	This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced NK cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK cell PVRIG expression levels were not increased. To understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumour cell recognition, cytokines (IL-2 and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum (ER) and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti- PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIGPVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML.
MeSH term(s)	Humans ; Immune Checkpoint Proteins ; Immunotherapy ; Killer Cells, Natural ; Leukemia, Myeloid, Acute ; Lymphocyte Activation ; Receptors, Cell Surface ; Receptors, Natural Killer Cell
Chemical Substances	Immune Checkpoint Proteins ; PVRIG protein, human ; Receptors, Cell Surface ; Receptors, Natural Killer Cell
Language	English
Publishing date	2021-12-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2020.258574
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Article ; Online: The efficacy of combination treatment with elotuzumab and lenalidomide is dependent on crosstalk between natural killer cells, monocytes and myeloma cells.

Richardson, Kelden / Keam, Simon P / Zhu, Joe Jiang / Meyran, Deborah / D'Souza, Criselle / Macdonald, Sean / Campbell, Kerry / Robbins, Michael / Bezman, Natalie A / Todd, Kirsten / Quach, Hang / Ritchie, David S / Harrison, Simon J / Prince, H Miles / Trapani, Joseph A / Jenkins, Misty R / Beavis, Paul A / Darcy, Phillip K / Neeson, Paul J

Haematologica

2023 Volume 108, Issue 1, Page(s) 83–97

Abstract: Patients with refractory relapsed multiple myeloma respond to combination treatment with elotuzumab and lenalidomide. The mechanisms underlying this observation are not fully understood. Furthermore, biomarkers predictive of response have not been ... ...

Abstract	Patients with refractory relapsed multiple myeloma respond to combination treatment with elotuzumab and lenalidomide. The mechanisms underlying this observation are not fully understood. Furthermore, biomarkers predictive of response have not been identified to date. To address these issues, we used a humanized myeloma mouse model and adoptive transfer of human natural killer (NK) cells to show that elotuzumab and lenalidomide treatment controlled myeloma growth, and this was mediated through CD16 on NK cells. In co-culture studies, we showed that peripheral blood mononuclear cells from a subset of patients with refractory relapsed multiple myeloma were effective killers of OPM2 myeloma cells when treated with elotuzumab and lenalidomide, and this was associated with significantly increased expression of CD54 on OPM2 cells. Furthermore, elotuzumab- and lenalidomide-induced OPM2 cell killing and increased OPM2 CD54 expression were dependent on both monocytes and NK cells, and these effects were not mediated by soluble factors alone. At the transcript level, elotuzumab and lenalidomide treatment significantly increased OPM2 myeloma cell expression of genes for trafficking and adhesion molecules, NK cell activation ligands and antigen presentation molecules. In conclusion, our findings suggest that multiple myeloma patients require elotuzumab- and lenalidomide-mediated upregulation of CD54 on autologous myeloma cells, in combination with NK cells and monocytes to mediate an effective anti-tumor response. Furthermore, our data suggest that increased myeloma cell CD54 expression levels could be a powerful predictive biomarker for response to elotuzumab and lenalidomide treatment.
MeSH term(s)	Animals ; Mice ; Humans ; Lenalidomide/pharmacology ; Lenalidomide/therapeutic use ; Lenalidomide/metabolism ; Multiple Myeloma/metabolism ; Monocytes/metabolism ; Leukocytes, Mononuclear/metabolism ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Killer Cells, Natural ; Dexamethasone/therapeutic use
Chemical Substances	Lenalidomide (F0P408N6V4) ; elotuzumab (1351PE5UGS) ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2023-01-01
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2021.279930
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