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Article ; Online: Radiation Therapy and Myeloid-Derived Suppressor Cells: Breaking Down Their Cancerous Partnership.

Bergerud, Kyra M Boorsma / Berkseth, Matthew / Pardoll, Drew M / Ganguly, Sudipto / Kleinberg, Lawrence R / Lawrence, Jessica / Odde, David J / Largaespada, David A / Terezakis, Stephanie A / Sloan, Lindsey

International journal of radiation oncology, biology, physics

2023 Volume 119, Issue 1, Page(s) 42–55

Abstract: Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived ... ...

Abstract	Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). MDSCs inhibit antitumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSCs interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSCs. RT activation of the cGAS-STING cytosolic DNA sensing pathway recruits MDSCs through a CCR2-mediated mechanism, inhibiting the production of type 1 interferons and hampering antitumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 and vascular endothelial growth factor mobilizes MDSCs to the TME. After recruitment, MDSCs promote immunosuppression by releasing reactive oxygen species and upregulating nitric oxide production through inducible nitric oxide synthase expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSCs degrades L-arginine and downregulates CD3ζ, inhibiting T-cell receptor reactivity. This review explains how radiation promotes tumor resistance through activation of immunosuppressive MDSCs in the TME and discusses current research targeting MDSCs, which could serve as a promising clinical treatment strategy in the future.
MeSH term(s)	Humans ; Myeloid-Derived Suppressor Cells/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Neoplasms/pathology ; Tumor Microenvironment ; Immunosuppressive Agents ; Hypoxia/metabolism
Chemical Substances	Vascular Endothelial Growth Factor A ; Immunosuppressive Agents
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	197614-x
ISSN	1879-355X ; 0360-3016
ISSN (online)	1879-355X
ISSN	0360-3016
DOI	10.1016/j.ijrobp.2023.11.050
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Article ; Online: Therapeutic Targeting of Checkpoint Receptors within the DNAM1 Axis.

Alteber, Zoya / Kotturi, Maya F / Whelan, Sarah / Ganguly, Sudipto / Weyl, Emmanuel / Pardoll, Drew M / Hunter, John / Ophir, Eran

Cancer discovery

2021 Volume 11, Issue 5, Page(s) 1040–1051

Abstract: Therapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. However, relapse following early response, attributable to primary and adaptive resistance, is ... ...

Abstract	Therapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. However, relapse following early response, attributable to primary and adaptive resistance, is frequently observed. Additional immunomodulatory pathways are being studied in patients with primary or acquired resistance to CTLA4 or PD-1 blockade. The DNAM1 axis is a potent coregulator of innate and adaptive immunity whose other components include the immunoglobulin receptors TIGIT, PVRIG, and CD96, and their nectin and nectin-like ligands. We review the basic biology and therapeutic relevance of this family, which has begun to show promise in cancer clinical trials. SIGNIFICANCE: Recent studies have outlined the immuno-oncologic ascendancy of coinhibitory receptors in the DNAM1 axis such as TIGIT and PVRIG and, to a lesser extent, CD96. Biological elucidation backed by ongoing clinical trials of single-agent therapy directed against TIGIT or PVRIG is beginning to provide the rationale for testing combination regimens of DNAM1 axis blockers in conjunction with anti-PD-1/PD-L1 agents.
MeSH term(s)	Antibodies, Monoclonal/therapeutic use ; Antigens, Differentiation, T-Lymphocyte/metabolism ; Humans ; Immunotherapy ; Neoplasms/drug therapy ; Receptors, Immunologic/metabolism
Chemical Substances	Antibodies, Monoclonal ; Antigens, Differentiation, T-Lymphocyte ; CD226 antigen ; Receptors, Immunologic
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-20-1248
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Article: Excyt: a graphical user interface for streamlining analysis of high-dimensional cytometry data

Sidhom, John-William / Theodros, Debebe / Murter, Benjamin / Zarif, Jelani C / Ganguly, Sudipto / Pardoll, Drew M / Baras, Alexander

Journal of visualized experiments. 2019 Jan. 16, , no. 143

2019

Abstract: With the advent of flow cytometers capable of measuring an increasing number of parameters, scientists continue to develop larger panels to phenotypically explore characteristics of their cellular samples. However, these technological advancements yield ... ...

Abstract	With the advent of flow cytometers capable of measuring an increasing number of parameters, scientists continue to develop larger panels to phenotypically explore characteristics of their cellular samples. However, these technological advancements yield high-dimensional data sets that have become increasingly difficult to analyze objectively within traditional manual-based gating programs. In order to better analyze and present data, scientists partner with bioinformaticians with expertise in analyzing high-dimensional data to parse their flow cytometry data. While these methods have been shown to be highly valuable in studying flow cytometry, they have yet to be incorporated in a straightforward and easy-to-use package for scientists who lack computational or programming expertise. To address this need, we have developed ExCYT, a MATLAB-based Graphical User Interface (GUI) that streamlines the analysis of high-dimensional flow cytometry data by implementing commonly employed analytical techniques for high-dimensional data including dimensionality reduction by t-SNE, a variety of automated and manual clustering methods, heatmaps, and novel high-dimensional flow plots. Additionally, ExCYT provides traditional gating options of select populations of interest for further t-SNE and clustering analysis as well as the ability to apply gates directly on t-SNE plots. The software provides the additional advantage of working with either compensated or uncompensated FCS files. In the event that post-acquisition compensation is required, the user can choose to provide the program a directory of single stains and an unstained sample. The program detects positive events in all channels and uses this select data to more objectively calculate the compensation matrix. In summary, ExCYT provides a comprehensive analysis pipeline to take flow cytometry data in the form of FCS files and allow any individual, regardless of computational training, to use the latest algorithmic approaches in understanding their data.
Keywords	automation ; cluster analysis ; computer software ; data collection ; flow cytometry ; user interface
Language	English
Dates of publication	2019-0116
Size	p. e57473.
Publishing place	Journal of Visualized Experiments
Document type	Article
ISSN	1940-087X
DOI	10.3791/57473
Database	NAL-Catalogue (AGRICOLA)

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Article: Situational aldehyde dehydrogenase expression by regulatory T cells may explain the contextual duality of cyclophosphamide as both a pro-inflammatory and tolerogenic agent.

Kanakry, Christopher G / Ganguly, Sudipto / Luznik, Leo

Oncoimmunology

2015 Volume 4, Issue 3, Page(s) e974393

Abstract: In two recent publications, we demonstrated that after allogeneic stimulation, regulatory T cells ( ... ...

Abstract	In two recent publications, we demonstrated that after allogeneic stimulation, regulatory T cells (T
Language	English
Publishing date	2015-03-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.4161/2162402X.2014.974393
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Article ; Online: Autologous Protein Solution processing alters lymphoid and myeloid cell populations and modulates gene expression dependent on cell type.

Peña, Alexis N / Sommerfeld, Sven D / Anderson, Amy E / Han, Jin / Maestas, David R / Mejias, Joscelyn C / Woodell-May, Jennifer / King, William / Ganguly, Sudipto / Elisseeff, Jennifer H

Arthritis research & therapy

2022 Volume 24, Issue 1, Page(s) 221

Abstract: Osteoarthritis (OA) is a degenerative disease associated with cartilage degradation, osteophyte formation, and fibrillation. Autologous Protein Solution (APS), a type of autologous anti-inflammatory orthobiologic, is used for pain management and ... ...

Abstract	Osteoarthritis (OA) is a degenerative disease associated with cartilage degradation, osteophyte formation, and fibrillation. Autologous Protein Solution (APS), a type of autologous anti-inflammatory orthobiologic, is used for pain management and treatment of OA. Various compositions of autologous PRP formulations are in clinical use for musculoskeletal pathologies, by nature of their minimal processing and source of bioactive molecules. Currently, there is no consensus on the optimal composition of the complex mixture. In this study, we focused on elucidating the immune cell subtypes and phenotypes in APS. We identified the immune cell types in APS from healthy donors and investigated phenotypic changes in the immune cells after APS processing. Based on flow cytometric analysis, we found that neutrophils and T cells are the most abundant immune cell types in APS, while monocytes experience the largest fold change in concentration compared to WBCs. Gene expression profiling revealed that APS processing results in differential gene expression changes dependent on immune cell type, with the most significantly differentially regulated genes occurring in the monocytes. Our results demonstrate that the mechanical processing of blood, whose main purpose is enrichment and separation, can alter its protein and cellular composition, as well as cellular phenotypes in the final product.
MeSH term(s)	Anti-Inflammatory Agents/therapeutic use ; Gene Expression ; Humans ; Leukocytes ; Monocytes ; Osteoarthritis/pathology
Chemical Substances	Anti-Inflammatory Agents
Language	English
Publishing date	2022-09-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/s13075-022-02875-x
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Zs.A 5490: Show issues

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Article ; Online: ExCYT: A Graphical User Interface for Streamlining Analysis of High-Dimensional Cytometry Data.

Sidhom, John-William / Theodros, Debebe / Murter, Benjamin / Zarif, Jelani C / Ganguly, Sudipto / Pardoll, Drew M / Baras, Alexander

Journal of visualized experiments : JoVE

2019 , Issue 143

Abstract	With the advent of flow cytometers capable of measuring an increasing number of parameters, scientists continue to develop larger panels to phenotypically explore characteristics of their cellular samples. However, these technological advancements yield high-dimensional data sets that have become increasingly difficult to analyze objectively within traditional manual-based gating programs. In order to better analyze and present data, scientists partner with bioinformaticians with expertise in analyzing high-dimensional data to parse their flow cytometry data. While these methods have been shown to be highly valuable in studying flow cytometry, they have yet to be incorporated in a straightforward and easy-to-use package for scientists who lack computational or programming expertise. To address this need, we have developed ExCYT, a MATLAB-based Graphical User Interface (GUI) that streamlines the analysis of high-dimensional flow cytometry data by implementing commonly employed analytical techniques for high-dimensional data including dimensionality reduction by t-SNE, a variety of automated and manual clustering methods, heatmaps, and novel high-dimensional flow plots. Additionally, ExCYT provides traditional gating options of select populations of interest for further t-SNE and clustering analysis as well as the ability to apply gates directly on t-SNE plots. The software provides the additional advantage of working with either compensated or uncompensated FCS files. In the event that post-acquisition compensation is required, the user can choose to provide the program a directory of single stains and an unstained sample. The program detects positive events in all channels and uses this select data to more objectively calculate the compensation matrix. In summary, ExCYT provides a comprehensive analysis pipeline to take flow cytometry data in the form of FCS files and allow any individual, regardless of computational training, to use the latest algorithmic approaches in understanding their data.
MeSH term(s)	Algorithms ; Flow Cytometry/methods ; Humans ; Lymphocytes/metabolism ; Myeloid Cells/metabolism ; Phenotype ; Software ; Staining and Labeling ; User-Computer Interface
Language	English
Publishing date	2019-01-16
Publishing country	United States
Document type	Journal Article ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/57473
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Article ; Online: Age-associated Senescent - T Cell Signaling Promotes Type 3 Immunity that Inhibits the Biomaterial Regenerative Response.

Advanced materials (Deerfield Beach, Fla.)

2023 , Page(s) e2310476

Abstract: Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and can potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and ... ...

Abstract	Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and can potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and regenerative medicine therapies remain unknown. Here, it is characterized how aging induces changes in immunological signatures that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix. Signatures of inflammation and interleukin (IL)-17 signaling increased with injury and treatment both locally and regionally in aged animals, and computational analysis uncovered age-associated senescent-T cell communication that promotes type 3 immunity in T cells. Local inhibition of type 3 immune activation using IL17-neutralizing antibodies improves healing and restores therapeutic response to the regenerative biomaterial, promoting muscle repair in older animals. These results provide insights into tissue immune dysregulation that occurs with aging that can be targeted to rejuvenate repair.
Language	English
Publishing date	2023-12-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1474949-X
ISSN	1521-4095 ; 0935-9648
ISSN (online)	1521-4095
ISSN	0935-9648
DOI	10.1002/adma.202310476
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Article ; Online: Divergent immune responses to synthetic and biological scaffolds.

Sadtler, Kaitlyn / Wolf, Matthew T / Ganguly, Sudipto / Moad, Christopher A / Chung, Liam / Majumdar, Shoumyo / Housseau, Franck / Pardoll, Drew M / Elisseeff, Jennifer H

Biomaterials

2018 Volume 192, Page(s) 405–415

Abstract: The immune system plays a critical role in wound healing and the response to biomaterials. Biomaterials-directed regenerative immunology is an immunoengineering strategy that targets the immune system to promote tissue repair. Biomaterial scaffolds ... ...

Abstract	The immune system plays a critical role in wound healing and the response to biomaterials. Biomaterials-directed regenerative immunology is an immunoengineering strategy that targets the immune system to promote tissue repair. Biomaterial scaffolds employed in regenerative medicine can be broadly classified as biological (such as those derived from the tissue extracellular matrix) or synthetic. Here, we show in depth the divergent myeloid response to biological versus synthetic biomaterial scaffolds. While neutrophil depletion and changes in physical properties such as shape and mechanics can modulate the pro-inflammatory myeloid immune response to synthetic materials to a degree, the overall general divergent myeloid responses persist. Biologic scaffolds elicit a type-2-like immune response with upregulation of genes such as Il4, Cd163, Mrc1 and Chil3, as well as genes associated with damage-associated molecular patterns providing another possible mechanism by which ECM scaffolds promote wound healing via amplification of endogenous wound-associated signaling pathways. Synthetic materials recruit a high proportion of neutrophils which is compounded by material stiffness and by the presence of an injury. Understanding the complex immune response to biomaterial classes will help in the efficient design of immunoengineering strategies and optimizing regenerative and reducing foreign body fibrotic responses to scaffolds.
MeSH term(s)	Animals ; Biocompatible Materials/adverse effects ; Biocompatible Materials/chemistry ; Female ; Immunity ; Inflammation/etiology ; Inflammation/immunology ; Macrophages/immunology ; Mice, Inbred C57BL ; Tissue Scaffolds/adverse effects ; Tissue Scaffolds/chemistry
Chemical Substances	Biocompatible Materials
Language	English
Publishing date	2018-11-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2018.11.002
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Article: Transcriptional profiling of tumor associated macrophages in human renal cell carcinoma reveals significant heterogeneity and opportunity for immunomodulation.

Nirschl, Thomas R / El Asmar, Margueritta / Ludwig, Wesley W / Ganguly, Sudipto / Gorin, Michael A / Johnson, Michael H / Pierorazio, Phillip M / Drake, Charles G / Allaf, Mohamad E / Zarif, Jelani C

American journal of clinical and experimental urology

2020 Volume 8, Issue 1, Page(s) 48–58

Abstract: Among the more notable immunotherapies are checkpoint inhibitors, which prevent suppressive signaling on T cells, thereby (re)activating them to kill tumor cells. Despite remarkable treatment responses to immune checkpoint blockade, with a subset of ... ...

Abstract	Among the more notable immunotherapies are checkpoint inhibitors, which prevent suppressive signaling on T cells, thereby (re)activating them to kill tumor cells. Despite remarkable treatment responses to immune checkpoint blockade, with a subset of patients achieving complete responses, a large population have little-to-no response, dictating the necessity of further research in this field. Myeloid derived cells heavily infiltrate the tumor microenvironment (TME) of many cancers and are believed to have a number of potent anti-inflammatory effects. Here we use primary non-metastatic renal cell carcinoma to interrogate the gene expression profiles of M2-tumor associated macrophages (M2-TAMs). We performed Fluorescent Activated Cell (FACS) sorting on monocytes from the peripheral blood and tumors of fresh clear cell renal cell carcinoma (ccRCC) samples obtained after patients underwent a partial (7 patients-87.5%) or radical (1 patient-12.5%) nephrectomy. We then utilized NanoString gene expression profiling to show that TAMs express a heterogeneous transcriptional profile that does not cleanly fit into the traditional M1-M2 TAM paradigm. We identified expression of M1 associated costimulatory molecules, a multitude of diverse chemokines, canonical M2 associated molecules, as well as factors involved in the Complement system and checkpoint receptors. Our data are in agreement with other published literature investigating TAMs in various non-ccRCC TMEs, and support the growing literature concerning expression of Complement factors and checkpoint receptors on TAMs.
Language	English
Publishing date	2020-02-25
Publishing country	United States
Document type	Journal Article
ISSN	2330-1910
ISSN	2330-1910
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Article ; Online: Effects of B cell-activating factor on tumor immunity.

Yarchoan, Mark / Ho, Won Jin / Mohan, Aditya / Shah, Yajas / Vithayathil, Teena / Leatherman, James / Dennison, Lauren / Zaidi, Neeha / Ganguly, Sudipto / Woolman, Skylar / Cruz, Kayla / Armstrong, Todd D / Jaffee, Elizabeth M

JCI insight

2020 Volume 5, Issue 10

Abstract: Immunotherapies that modulate T cell function have been firmly established as a pillar of cancer therapy, whereas the potential for B cells in the antitumor immune response is less established. B cell-activating factor (BAFF) is a B cell-activating ... ...

Abstract	Immunotherapies that modulate T cell function have been firmly established as a pillar of cancer therapy, whereas the potential for B cells in the antitumor immune response is less established. B cell-activating factor (BAFF) is a B cell-activating cytokine belonging to the TNF ligand family that has been associated with autoimmunity, but little is known about its effects on cancer immunity. We find that BAFF upregulates multiple B cell costimulatory molecules; augments IL-12a expression, consistent with Be-1 lineage commitment; and enhances B cell antigen-presentation to CD4+ Th cells in vitro. In a syngeneic mouse model of melanoma, BAFF upregulates B cell CD40 and PD-L1 expression; it also modulates T cell function through increased T cell activation and TH1 polarization, enhanced expression of the proinflammatory leukocyte trafficking chemokine CCR6, and promotion of a memory phenotype, leading to enhanced antitumor immunity. Similarly, adjuvant BAFF promotes a memory phenotype of T cells in vaccine-draining lymph nodes and augments the antitumor efficacy of whole cell vaccines. BAFF also has distinct immunoregulatory functions, promoting the expansion of CD4+Foxp3+ Tregs in the spleen and tumor microenvironment (TME). Human melanoma data from The Cancer Genome Atlas (TCGA) demonstrate that BAFF expression is positively associated with overall survival and a TH1/IFN-γ gene signature. These data support a potential role for BAFF signaling as a cancer immunotherapy.
MeSH term(s)	Animals ; B-Cell Activating Factor/genetics ; B-Cell Activating Factor/immunology ; Immunity, Cellular ; Interferon-gamma/immunology ; Interleukin-12 Subunit p35/genetics ; Interleukin-12 Subunit p35/immunology ; Melanoma, Experimental/genetics ; Melanoma, Experimental/immunology ; Melanoma, Experimental/pathology ; Mice ; T-Lymphocytes, Regulatory/immunology ; Th1 Cells/immunology
Chemical Substances	B-Cell Activating Factor ; IFNG protein, mouse ; Il12a protein, mouse ; Interleukin-12 Subunit p35 ; Tnfsf13b protein, mouse ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2020-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.136417
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