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Article ; Online: Cancer-targeted photoimmunotherapy induces antitumor immunity and can be augmented by anti-PD-1 therapy for durable anticancer responses in an immunologically active murine tumor model.

Hsu, Michelle A / Okamura, Stephanie M / De Magalhaes Filho, C Daniel / Bergeron, Daniele M / Rodriguez, Ahiram / West, Melissa / Yadav, Deepak / Heim, Roger / Fong, Jerry J / Garcia-Guzman, Miguel

Cancer immunology, immunotherapy : CII

2022 Volume 72, Issue 1, Page(s) 151–168

Abstract: The complex immunosuppressive nature of solid tumor microenvironments poses a significant challenge to generating efficacious and durable anticancer responses. Photoimmunotherapy is a cancer treatment strategy by which an antibody is conjugated with a ... ...

Abstract	The complex immunosuppressive nature of solid tumor microenvironments poses a significant challenge to generating efficacious and durable anticancer responses. Photoimmunotherapy is a cancer treatment strategy by which an antibody is conjugated with a non-toxic light-activatable dye. Following administration of the conjugate and binding to the target tumor, subsequent local laser illumination activates the dye, resulting in highly specific target cell membrane disruption. Here we demonstrate that photoimmunotherapy treatment elicited tumor necrosis, thus inducing immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs). Photoimmunotherapy-killed tumor cells activated dendritic cells (DC), leading to the production of proinflammatory cytokines, T cell stimulation, priming antigen-specific T cells, and durable memory T cell responses, which led complete responder mice to effectively reject new tumors upon rechallenge. PD-1 blockade in combination with photoimmunotherapy enhanced overall anticancer efficacy, including against anti-PD-1-resistant tumors. The combination treatment also elicited abscopal anticancer activity, as observed by reduction of distal, non-illuminated tumors, further demonstrating the ability of photoimmunotherapy to harness local and peripheral T cell responses. With this work we therefore delineate the immune mechanisms of action for photoimmunotherapy and demonstrate the potential for cancer-targeted photoimmunotherapy to be combined with other immunotherapy approaches for augmented, durable anticancer efficacy. Moreover, we demonstrate responses utilizing various immunocompetent mouse models, as well as in vitro data from human cells, suggesting broad translational potential.
MeSH term(s)	Humans ; Animals ; Mice ; Immunotherapy/methods ; Phototherapy/methods ; Neoplasms/therapy ; Disease Models, Animal ; Cell Line, Tumor ; Tumor Microenvironment
Language	English
Publishing date	2022-07-01
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/s00262-022-03239-9
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Article: Human-specific evolutionary changes in the biology of siglecs.

Schwarz, Flavio / Fong, Jerry J / Varki, Ajit

Advances in experimental medicine and biology

2014 Volume 842, Page(s) 1–16

MeSH term(s)	Chromosome Mapping ; Evolution, Molecular ; Genetic Predisposition to Disease/genetics ; Humans ; Multigene Family ; Protein Isoforms/genetics ; Receptors, Cell Surface/classification ; Receptors, Cell Surface/genetics ; Sialic Acid Binding Immunoglobulin-like Lectins/classification ; Sialic Acid Binding Immunoglobulin-like Lectins/genetics
Chemical Substances	Protein Isoforms ; Receptors, Cell Surface ; Sialic Acid Binding Immunoglobulin-like Lectins
Language	English
Publishing date	2014-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-319-11280-0_1
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Article ; Online: Siglec-7 engagement by GBS β-protein suppresses pyroptotic cell death of natural killer cells.

Fong, Jerry J / Tsai, Chih-Ming / Saha, Sudeshna / Nizet, Victor / Varki, Ajit / Bui, Jack D

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

2018 Volume 115, Issue 41, Page(s) 10410–10415

Abstract: Natural killer (NK) cells are innate immune lymphocytes that recognize and destroy abnormal host cells, such as tumor cells or those infected by viral pathogens. To safely accomplish these functions, NK cells display activating receptors that detect ... ...

Abstract	Natural killer (NK) cells are innate immune lymphocytes that recognize and destroy abnormal host cells, such as tumor cells or those infected by viral pathogens. To safely accomplish these functions, NK cells display activating receptors that detect stress molecules or viral ligands displayed at the cell surface, balanced by inhibitory receptors that bind to self-molecules. To date, such activating and inhibitory receptors on NK cells are not known to recognize bacterial determinants. Moreover, NK cell responses to direct interactions with extracellular bacteria are poorly explored. In this study, we observed the human neonatal pathogen group B
MeSH term(s)	Antigens, Differentiation, Myelomonocytic/genetics ; Antigens, Differentiation, Myelomonocytic/metabolism ; Cells, Cultured ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Humans ; Immunity, Innate/immunology ; Inflammation Mediators/metabolism ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Killer Cells, Natural/pathology ; Lectins/genetics ; Lectins/metabolism ; Pyroptosis
Chemical Substances	Antigens, Differentiation, Myelomonocytic ; DNA-Binding Proteins ; Inflammation Mediators ; Lectins ; SIGLEC7 protein, human ; beta protein, Streptococcus
Language	English
Publishing date	2018-09-25
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.1804108115
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Article: Evolution of the exclusively human pathogen

Landig, Corinna S / Hazel, Ashley / Kellman, Benjamin P / Fong, Jerry J / Schwarz, Flavio / Agarwal, Sarika / Varki, Nissi / Massari, Paola / Lewis, Nathan E / Ram, Sanjay / Varki, Ajit

Evolutionary applications

2019 Volume 12, Issue 2, Page(s) 337–349

Abstract: Neisseria ... ...

Abstract	Neisseria gonorrhoeae
Language	English
Publishing date	2019-01-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2405496-3
ISSN	1752-4563 ; 1752-4571
ISSN (online)	1752-4563
ISSN	1752-4571
DOI	10.1111/eva.12744
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Article ; Online: Siglec-14 Enhances NLRP3-Inflammasome Activation in Macrophages.

Tsai, Chih-Ming / Riestra, Angelica M / Ali, Syed Raza / Fong, Jerry J / Liu, Janet Z / Hughes, Gillian / Varki, Ajit / Nizet, Victor

Journal of innate immunity

2019 Volume 12, Issue 4, Page(s) 333–343

Abstract: Pathogenic microorganisms are sensed by the inflammasome, resulting in the release of the pro-immune and proinflammatory cytokine interleukin-1β (IL-1β). In humans, the paired ... s ... ialic acid-binding Ig-like lectin receptors Siglec-5 ( ... ...

Abstract	Pathogenic microorganisms are sensed by the inflammasome, resulting in the release of the pro-immune and proinflammatory cytokine interleukin-1β (IL-1β). In humans, the paired <underline>s</underline>ialic acid-binding Ig-like lectin receptors Siglec-5 (inhibitory) and Siglec-14 (activating) have been shown to have reciprocal roles in regulating macrophage immune responses, but their interaction with IL-1β signaling and the inflammasome has not been characterized. Here we show that in response to known inflammasome activators (ATP, nigericin) or the sialic acid-expressing human bacterial pathogen group B Streptococcus (GBS), the presence of Siglec-14 enhances, whereas Siglec-5 reduces, inflammasome activation and macrophage IL-1β release. Human THP-1 macrophages stably transfected with Siglec-14 exhibited increased caspase-1 activation, IL-1β release and pyroptosis after GBS infection, in a manner blocked by a specific inhibitor of nucleotide-binding domain leucine-rich repeat protein 3 (NLRP3), a protein involved in inflammasome assembly. Another leading pathogen, Streptococcus pneumoniae, lacks sialic acid but rather prominently expresses a sialidase, which cleaves sialic acid from macrophages, eliminating cis- interactions with the lectin receptor, thus attenuating Siglec-14 induced IL-1β secretion. Vimentin, a cytoskeletal protein released during macrophage inflammatory activation is known to induce the inflammasome. We found that vimentin has increased interaction with Siglec-14 compared to Siglec-5, and this interaction heightened IL-1β production by Siglec-14-expressing cells. Siglec-14 is absent from some humans because of a SIGLEC5/14 fusion polymorphism, and we found increased IL-1β expression in primary macrophages from SIGLEC14+/+ individuals compared to those with the SIGLEC14-/+ and SIGLEC14-/- genotypes. Collectively, our results identify a new immunoregulatory role of Siglec-14 as a positive regulator of NLRP3 inflammasome activation.
MeSH term(s)	Humans ; Inflammasomes/genetics ; Inflammasomes/immunology ; Lectins/genetics ; Lectins/immunology ; Macrophages/immunology ; Macrophages/microbiology ; Macrophages/pathology ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/immunology ; Streptococcal Infections/genetics ; Streptococcal Infections/immunology ; Streptococcal Infections/pathology ; Streptococcus agalactiae/immunology ; THP-1 Cells
Chemical Substances	Inflammasomes ; Lectins ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRP3 protein, human ; Receptors, Cell Surface ; SIGLEC14 protein, human
Language	English
Publishing date	2019-12-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2454158-8
ISSN	1662-8128 ; 1662-811X
ISSN (online)	1662-8128
ISSN	1662-811X
DOI	10.1159/000504323
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Article ; Online: Vocabulary Growth: Dual Language Learners at Risk for Language Impairment.

Kan, Pui Fong / Huang, Shirley / Winicour, Ellie / Yang, Jerry

American journal of speech-language pathology

2020 Volume 29, Issue 3, Page(s) 1178–1195

Abstract: Purpose This research project examined the vocabulary growth patterns of typically developing (TD) Cantonese-English dual language learners (DLLs) and their peers who are at risk for language impairment. Method Two studies were done. Study 1 examined the ...

Abstract	Purpose This research project examined the vocabulary growth patterns of typically developing (TD) Cantonese-English dual language learners (DLLs) and their peers who are at risk for language impairment. Method Two studies were done. Study 1 examined the concurrent validity of a pilot vocabulary screening measure, the Kai Ming Vocabulary Test, that was designed for Cantonese-English preschool DLLs. Participants were 53 preschool children who learned Cantonese as their first language (L1) and English as a second language (L2). Their scores on the Kai Ming Vocabulary Test were examined in relation to their language sample measures, including number of different words and mean length of utterance, in L1 and in L2. Study 2 examined the vocabulary growth patterns of 24 TD Cantonese-English DLL preschoolers and 24 DLLs who are at risk for language impairment (At-Risk group). Each child was tested 3 times during an academic year. Results Results of Study 1 showed that children's vocabulary scores (
MeSH term(s)	Child ; Child Language ; Child, Preschool ; Humans ; Language ; Language Development Disorders/diagnosis ; Language Tests ; Multilingualism ; Vocabulary
Language	English
Publishing date	2020-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1154406-5
ISSN	1558-9110 ; 1058-0360
ISSN (online)	1558-9110
ISSN	1058-0360
DOI	10.1044/2020_AJSLP-19-00160
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Article ; Online: Evolution of the exclusively human pathogen Neisseria gonorrhoeae

Corinna S. Landig / Ashley Hazel / Benjamin P. Kellman / Jerry J. Fong / Flavio Schwarz / Sarika Agarwal / Nissi Varki / Paola Massari / Nathan E. Lewis / Sanjay Ram / Ajit Varki

Evolutionary Applications, Vol 12, Iss 2, Pp 337-

Human‐specific engagement of immunoregulatory Siglecs

2019 Volume 349

Abstract: Abstract Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhea exclusively in humans and uses multiple strategies to infect, including acquisition of host sialic acids that cap and mask lipooligosaccharide termini, while restricting ... ...

Abstract	Abstract Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhea exclusively in humans and uses multiple strategies to infect, including acquisition of host sialic acids that cap and mask lipooligosaccharide termini, while restricting complement activation. We hypothesized that gonococci selectively target human anti‐inflammatory sialic acid‐recognizing Siglec receptors on innate immune cells to blunt host responses and that pro‐inflammatory Siglecs and SIGLEC pseudogene polymorphisms represent host evolutionary adaptations to counteract this interaction. N. gonorrhoeae can indeed engage multiple human but not chimpanzee CD33rSiglecs expressed on innate immune cells and in the genitourinary tract––including Siglec‐11 (inhibitory) and Siglec‐16 (activating), which we detected for the first time on human cervical epithelium. Surprisingly, in addition to LOS sialic acid, we found that gonococcal porin (PorB) mediated binding to multiple Siglecs. PorB also bound preferentially to human Siglecs and not chimpanzee orthologs, modulating host immune reactions in a human‐specific manner. Lastly, we studied the distribution of null SIGLEC polymorphisms in a Namibian cohort with a high prevalence of gonorrhea and found that uninfected women preferentially harbor functional SIGLEC16 alleles encoding an activating immune receptor. These results contribute to the understanding of the human specificity of N. gonorrhoeae and how it evolved to evade the human immune defense.
Keywords	disease biology ; evolutionary medicine ; gonorrhea ; microbial biology ; polymorphism ; population genetics ; Evolution ; QH359-425
Language	English
Publishing date	2019-02-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
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Article ; Online: Siglec-14 Enhances NLRP3-Inflammasome Activation in Macrophages

Chih-Ming Tsai / Angelica M. Riestra / Syed Raza Ali / Jerry J. Fong / Janet Z. Liu / Gillian Hughes / Ajit Varki / Victor Nizet

Journal of Innate Immunity, Pp 1-

2019 Volume 11

Abstract: Pathogenic microorganisms are sensed by the inflammasome, resulting in the release of the pro-immune and proinflammatory cytokine interleukin-1β (IL-1β). In humans, the paired sialic acid-binding Ig-like lectin receptors Siglec-5 (inhibitory) and Siglec- ... ...

Abstract	Pathogenic microorganisms are sensed by the inflammasome, resulting in the release of the pro-immune and proinflammatory cytokine interleukin-1β (IL-1β). In humans, the paired sialic acid-binding Ig-like lectin receptors Siglec-5 (inhibitory) and Siglec-14 (activating) have been shown to have reciprocal roles in regulating macrophage immune responses, but their interaction with IL-1β signaling and the inflammasome has not been characterized. Here we show that in response to known inflammasome activators (ATP, nigericin) or the sialic acid-expressing human bacterial pathogen group B Streptococcus (GBS), the presence of Siglec-14 enhances, whereas Siglec-5 reduces, inflammasome activation and macrophage IL-1β release. Human THP-1 macrophages stably transfected with Siglec-14 exhibited increased caspase-1 activation, IL-1β release and pyroptosis after GBS infection, in a manner blocked by a specific inhibitor of nucleotide-binding domain leucine-rich repeat protein 3 (NLRP3), a protein involved in inflammasome assembly. Another leading pathogen, Streptococcus pneumoniae, lacks sialic acid but rather prominently expresses a sialidase, which cleaves sialic acid from macrophages, eliminating cis- interactions with the lectin receptor, thus attenuating Siglec-14 induced IL-1β secretion. Vimentin, a cytoskeletal protein released during macrophage inflammatory activation is known to induce the inflammasome. We found that vimentin has increased interaction with Siglec-14 compared to Siglec-5, and this interaction heightened IL-1β production by Siglec-14-expressing cells. Siglec-14 is absent from some humans because of a SIGLEC5/14 fusion polymorphism, and we found increased IL-1β expression in primary macrophages from SIGLEC14+/+ individuals compared to those with the SIGLEC14–/+ and SIGLEC14–/– genotypes. Collectively, our results identify a new immunoregulatory role of Siglec-14 as a positive regulator of NLRP3 inflammasome activation.
Keywords	siglec ; interleukin-1β ; caspase-1 ; inflammasome ; macrophages ; innate immunity ; vimentin ; Medicine ; R ; Internal medicine ; RC31-1245
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Karger Publishers
Document type	Article ; Online
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Article ; Online: Determining subpopulation methylation profiles from bisulfite sequencing data of heterogeneous samples using DXM.

Fong, Jerry / Gardner, Jacob R / Andrews, Jared M / Cashen, Amanda F / Payton, Jacqueline E / Weinberger, Kilian Q / Edwards, John R

Nucleic acids research

2021 Volume 49, Issue 16, Page(s) e93

Abstract: Epigenetic changes, such as aberrant DNA methylation, contribute to cancer clonal expansion and disease progression. However, identifying subpopulation-level changes in a heterogeneous sample remains challenging. Thus, we have developed a computational ... ...

Abstract	Epigenetic changes, such as aberrant DNA methylation, contribute to cancer clonal expansion and disease progression. However, identifying subpopulation-level changes in a heterogeneous sample remains challenging. Thus, we have developed a computational approach, DXM, to deconvolve the methylation profiles of major allelic subpopulations from the bisulfite sequencing data of a heterogeneous sample. DXM does not require prior knowledge of the number of subpopulations or types of cells to expect. We benchmark DXM's performance and demonstrate improvement over existing methods. We further experimentally validate DXM predicted allelic subpopulation-methylation profiles in four Diffuse Large B-Cell Lymphomas (DLBCLs). Lastly, as proof-of-concept, we apply DXM to a cohort of 31 DLBCLs and relate allelic subpopulation methylation profiles to relapse. We thus demonstrate that DXM can robustly find allelic subpopulation methylation profiles that may contribute to disease progression using bisulfite sequencing data of any heterogeneous sample.
MeSH term(s)	Algorithms ; Cell Line, Tumor ; DNA Methylation ; Epigenomics/methods ; Epigenomics/standards ; Genetic Heterogeneity ; Humans ; Lymphoma, Large B-Cell, Diffuse/genetics ; Sequence Analysis, DNA/methods ; Sequence Analysis, DNA/standards
Language	English
Publishing date	2021-06-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkab516
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Article: Comparing feature selection and machine learning approaches for predicting

Frontiers in neuroinformatics

2024 Volume 17, Page(s) 1244336

Abstract: Introduction: Pharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information ... ...

Abstract	Introduction: Pharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information such as methylation into pharmacogenetic models holds the potential to improve their accuracy and consequently prescribing decisions. Cytochrome P450 2D6 ( Methods: Buffy coat DNA methylation was quantified using the Illumina Infinium Methylation EPIC beadchip. CpG sites associated with Results: Overall, Elastic Net models of genetic features appeared to perform marginally better than heritability estimates and substantially better than Linear Regression and XGBoost models. The addition of nongenetic features appeared to improve performance for some but not all feature sets and probes. The best feature set and Machine Learning (ML) approach differed substantially between CpG sites and a number of top variables were identified for each model. Discussion: The development of SNP-based prediction models for CYP2D6 CpG methylation in Singaporean children of varying ethnicities in this study has clinical application. With further validation, they may add to the set of tools available to improve precision medicine and pharmacogenetics-based dosing.
Language	English
Publishing date	2024-02-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452979-5
ISSN	1662-5196
ISSN	1662-5196
DOI	10.3389/fninf.2023.1244336
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