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Article ; Online: Facts and hopes in using omics to advance combined immunotherapy strategies.

Augustin, Ryan C / Cai, Wesley L / Luke, Jason J / Bao, Riyue

Clinical cancer research : an official journal of the American Association for Cancer Research

2024

Abstract: The field of oncology has been transformed by immune checkpoint inhibitors (ICI) and other immune-based agents, however many patients do not receive a durable benefit. While biomarker assessments from pivotal ICI trials have uncovered certain mechanisms ... ...

Abstract	The field of oncology has been transformed by immune checkpoint inhibitors (ICI) and other immune-based agents, however many patients do not receive a durable benefit. While biomarker assessments from pivotal ICI trials have uncovered certain mechanisms of resistance, results thus far have only scraped the surface. Mechanisms of resistance are as complex as the tumor microenvironment (TME) itself, and the development of effective therapeutic strategies will only be possible by building accurate models of the tumor-immune interface. With advancement of multi-omic technologies, high-resolution characterization of the TME is now possible. In addition to sequencing of bulk tumor, single-cell transcriptomic, proteomic, and epigenomic data as well as T cell receptor profiling can now be simultaneously measured and compared between responders and non-responders to ICI. Spatial sequencing and imaging platforms have further expanded the dimensionality of existing technologies. Rapid advancements in computation and data sharing strategies enables development of biologically interpretable machine learning models to integrate data from high-resolution, multi-omic platforms. These models catalyze the identification of resistance mechanisms and predictors of benefit in ICI-treated patients, providing scientific foundation for novel clinical trials. Moving forward, we propose a framework by which in silico screening, functional validation, and clinical trial biomarker assessment can be used for the advancement of combined immunotherapy strategies.
Language	English
Publishing date	2024-01-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-2241
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Article ; Online: Targeting Cbl-b in cancer immunotherapy.

Augustin, Ryan C / Bao, Riyue / Luke, Jason J

Journal for immunotherapy of cancer

2023 Volume 11, Issue 2

Abstract: Cancer immunotherapy with immune-checkpoint blockade has improved the outcomes of patients with various malignancies, yet a majority do not benefit or develop resistance. To address this unmet need, efforts across the field are targeting additional ... ...

Abstract	Cancer immunotherapy with immune-checkpoint blockade has improved the outcomes of patients with various malignancies, yet a majority do not benefit or develop resistance. To address this unmet need, efforts across the field are targeting additional coinhibitory receptors, costimulatory proteins, and intracellular mediators that could prevent or bypass anti-PD1 resistance mechanisms. The CD28 costimulatory pathway is necessary for antigen-specific T cell activation, though prior CD28 agonists did not translate successfully to clinic due to toxicity. Casitas B lymphoma-b (Cbl-b) is a downstream, master regulator of both CD28 and CTLA-4 signaling. This E3 ubiquitin ligase regulates both innate and adaptive immune cells, ultimately promoting an immunosuppressive tumor microenvironment (TME) in the absence of CD28 costimulation. Recent advances in pharmaceutical screening and computational biology have enabled the development of novel platforms to target this once 'undruggable' protein. These platforms include DNA encoded library screening, allosteric drug targeting, small-interfering RNA inhibition, CRISPR genome editing, and adoptive cell therapy. Both genetic knock-out models and Cbl-b inhibitors have been shown to reverse immunosuppression in the TME, stimulate cytotoxic T cell activity, and promote tumor regression, findings augmented with PD1 blockade in experimental models. In translating Cbl-b inhibitors to clinic, we propose specific gene expression profiles that may identify patient populations most likely to benefit. Overall, novel Cbl-b inhibitors provide antigen-specific immune stimulation and are a promising therapeutic tool in the field of immuno-oncology.
MeSH term(s)	Humans ; CD28 Antigens/metabolism ; Proto-Oncogene Proteins c-cbl/genetics ; Adaptor Proteins, Signal Transducing/genetics ; Immunotherapy ; Neoplasms ; Lymphoma ; Tumor Microenvironment
Chemical Substances	CD28 Antigens ; Proto-Oncogene Proteins c-cbl (EC 2.3.2.27) ; Adaptor Proteins, Signal Transducing
Language	English
Publishing date	2023-02-07
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-006007
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Article ; Online: Old Dog, New Trick: A Tumor-Intrinsic Role for PD-1 in Chemoresistant Tumor Subclones.

Augustin, Ryan C / Bao, Riyue / Luke, Jason J

Clinical cancer research : an official journal of the American Association for Cancer Research

2022 Volume 29, Issue 3, Page(s) 505–507

Abstract: Summary: Programmed cell death protein 1 (PD-1) is a well-known driver of immunosuppression and lymphocyte-associated disease progression. Increasing evidence suggests a tumor-intrinsic role for PD-1 in promoting chemoresistance via stem-like features. ... ...

Abstract	Summary: Programmed cell death protein 1 (PD-1) is a well-known driver of immunosuppression and lymphocyte-associated disease progression. Increasing evidence suggests a tumor-intrinsic role for PD-1 in promoting chemoresistance via stem-like features. Moving forward, a recent study implies a novel antitumor mechanism for PD-1 inhibition. See related article by Rotolo et al., p. 621.
MeSH term(s)	Humans ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Lung Neoplasms ; Lymphocytes/metabolism
Chemical Substances	Programmed Cell Death 1 Receptor
Language	English
Publishing date	2022-11-17
Publishing country	United States
Document type	Editorial ; Research Support, N.I.H., Extramural
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-3022
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Article: Genomic signatures of globally enhanced gene duplicate accumulation in the megadiverse higher Diptera fueling intralocus sexual conflict resolution.

Bao, Riyue / Friedrich, Markus

PeerJ

2020 Volume 8, Page(s) e10012

Abstract: Gene duplication is an important source of evolutionary innovation. To explore the relative impact of gene duplication during the diversification of major insect model system lineages, we performed a comparative analysis of lineage-specific gene ... ...

Abstract	Gene duplication is an important source of evolutionary innovation. To explore the relative impact of gene duplication during the diversification of major insect model system lineages, we performed a comparative analysis of lineage-specific gene duplications in the fruit fly
Language	English
Publishing date	2020-10-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2703241-3
ISSN	2167-8359
ISSN	2167-8359
DOI	10.7717/peerj.10012
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Article ; Online: Gestational sleep apnea perturbations induce metabolic disorders by divergent epigenomic regulation.

Cortese, Rene / Khalyfa, Abdelnaby / Bao, Riyue / Gozal, David

Epigenomics

2021 Volume 13, Issue 10, Page(s) 751–765

Abstract: Aim: ...

Abstract	Aim:
MeSH term(s)	Animals ; DNA Methylation ; Epigenesis, Genetic ; Epigenomics ; Female ; Hypoxia/genetics ; Intra-Abdominal Fat/metabolism ; Metabolic Diseases/genetics ; Mice, Inbred C57BL ; Obesity/genetics ; Phenotype ; Pregnancy ; Prenatal Exposure Delayed Effects/genetics ; Sleep Apnea Syndromes/genetics ; Mice
Language	English
Publishing date	2021-04-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2537199-X
ISSN	1750-192X ; 1750-1911
ISSN (online)	1750-192X
ISSN	1750-1911
DOI	10.2217/epi-2020-0435
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Article ; Online: Genomic signatures of globally enhanced gene duplicate accumulation in the megadiverse higher Diptera fueling intralocus sexual conflict resolution

Riyue Bao / Markus Friedrich

PeerJ, Vol 8, p e

2020 Volume 10012

Abstract	Gene duplication is an important source of evolutionary innovation. To explore the relative impact of gene duplication during the diversification of major insect model system lineages, we performed a comparative analysis of lineage-specific gene duplications in the fruit fly Drosophila melanogaster (Diptera: Brachycera), the mosquito Anopheles gambiae (Diptera: Culicomorpha), the red flour beetle Tribolium castaneum (Coleoptera), and the honeybee Apis mellifera (Hymenoptera). Focusing on close to 6,000 insect core gene families containing maximally six paralogs, we detected a conspicuously higher number of lineage-specific duplications in Drosophila (689) compared to Anopheles (315), Tribolium (386), and Apis (223). Based on analyses of sequence divergence, phylogenetic distribution, and gene ontology information, we present evidence that an increased background rate of gene duplicate accumulation played an exceptional role during the diversification of the higher Diptera (Brachycera), in part by providing enriched opportunities for intralocus sexual conflict resolution, which may have boosted speciation rates during the early radiation of the megadiverse brachyceran subclade Schizophora.
Keywords	Gene duplication ; Drosophila ; Brachycera ; Genome evolution ; Energy metabolism ; Sexual conflict resolution ; Medicine ; R ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	PeerJ Inc.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration.

Higgs, Emily F / Bao, Riyue / Hatogai, Ken / Gajewski, Thomas F

Journal for immunotherapy of cancer

2022 Volume 10, Issue 6

Abstract: Background: A T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration in ... ...

Abstract	Background: A T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration in tumors is critical for expanding immunotherapy efficacy. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade. Methods: RNA sequencing and clinical data were obtained for Wilms tumor, rhabdoid tumor, osteosarcoma, and neuroblastoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and adult cancers from The Cancer Genome Atlas (TCGA). Using an 18-gene tumor inflammation signature (TIS) representing activated CD8 Results: Among the four pediatric cancers, we observed the lowest TIS scores in Wilms tumor. TIS scores were lower in Wilms tumors compared with matched normal kidney tissues, arguing for loss of endogenous T cell infiltration. Pathway analysis of genes upregulated in Wilms tumor and anti-correlated with TIS revealed activated pathways involved DNA repair. The majority of adult tumors in TCGA also showed high DNA repair scores associated with low TIS. Melanoma samples from an independent cohort revealed an inverse correlation between MSH2 Conclusions: Increased tumor expression of DNA repair genes is associated with a less robust immune response in Wilms tumor and the majority of TCGA tumor types. Surprisingly, the negative relationship between DNA repair score and TIS remained strong across TCGA when correcting for mutation count, indicating a potential role for DNA repair genes outside of preventing the accumulation of mutations. While loss of DNA repair machinery has been associated with carcinogenesis and mutational antigen generation, our results suggest that hyperexpression of DNA repair genes might be prohibitive for antitumor immunity, arguing for pharmacologic targeting of DNA repair as a potential therapeutic strategy.
MeSH term(s)	Adult ; CD8-Positive T-Lymphocytes ; Child ; DNA Repair/genetics ; Humans ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/genetics ; Melanoma/genetics ; MutS Homolog 2 Protein/genetics ; Tumor Microenvironment/genetics ; Wilms Tumor/drug therapy ; Wilms Tumor/genetics
Chemical Substances	MutS Homolog 2 Protein (EC 3.6.1.3)
Language	English
Publishing date	2022-06-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-004797
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Article ; Online: PD-1 Blockade in Chinese versus Western Patients with Melanoma.

Shoushtari, Alexander N / Bao, Riyue / Luke, Jason J

Clinical cancer research : an official journal of the American Association for Cancer Research

2020 Volume 26, Issue 16, Page(s) 4171–4173

Abstract: In this trial of programmed cell death-1 (PD-1) blockade with toripalimab in previously treated Chinese patients with melanoma, unique histologic and molecular features may explain why the objective response rate is lower than those defined in Western ... ...

Abstract	In this trial of programmed cell death-1 (PD-1) blockade with toripalimab in previously treated Chinese patients with melanoma, unique histologic and molecular features may explain why the objective response rate is lower than those defined in Western populations. This work suggests future avenues for investigating mechanisms of melanoma formation and resistance to PD-1 blockade.
MeSH term(s)	Antibodies, Monoclonal, Humanized ; China ; Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Programmed Cell Death 1 Receptor
Chemical Substances	Antibodies, Monoclonal, Humanized ; Programmed Cell Death 1 Receptor ; toripalimab (8JXN261VVA)
Language	English
Publishing date	2020-06-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-20-1558
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Article ; Online: Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Riyue Bao / Daniel Stapor / Jason J. Luke

Genome Medicine, Vol 12, Iss 1, Pp 1-

2020 Volume 19

Abstract: Abstract Background The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational burden (TMB) may also dictate response, and some oncogenes ...

Abstract	Abstract Background The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational burden (TMB) may also dictate response, and some oncogenes (i.e., WNT/β-catenin) are known to mediate immunosuppression. Methods We performed an integrated multi-omic analysis of human cancer including 11,607 tumors across multiple databases and patients treated with anti-PD1. After adjusting for TMB, we correlated the T cell-inflamed gene expression signature with somatic mutations, transcriptional programs, and relevant proteome for different immune phenotypes, by tumor type and across cancers. Results Strong correlations were noted between mutations in oncogenes and tumor suppressor genes and non-T cell-inflamed tumors with examples including IDH1 and GNAQ as well as less well-known genes including KDM6A, CD11c, and genes with unknown functions. Conversely, we observe genes associating with the T cell-inflamed phenotype including VHL and PBRM1. Analyzing gene expression patterns, we identify oncogenic mediators of immune exclusion across cancer types (HIF1A and MYC) as well as novel examples in specific tumors such as sonic hedgehog signaling, hormone signaling and transcription factors. Using network analysis, somatic and transcriptomic events were integrated. In contrast to previous reports of individual tumor types such as melanoma, integrative pan-cancer analysis demonstrates that most non-T cell-inflamed tumors are influenced by multiple signaling pathways and that increasing numbers of co-activated pathways leads to more highly non-T cell-inflamed tumors. Validating these analyses, we observe highly consistent inverse relationships between pathway protein levels and the T cell-inflamed gene expression across cancers. Finally, we integrate available databases for drugs that might overcome or augment the identified mechanisms. Conclusions These results nominate molecular targets and drugs potentially available ...
Keywords	T cell-inflamed ; Immune evasion ; Genomics ; Transcriptomics ; TCGA ; Medicine ; R ; Genetics ; QH426-470
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evolutionary conservation of opsin gene expression patterns in the compound eyes of darkling beetles.

Wu, Meng / Bao, Riyue / Friedrich, Markus

Development genes and evolution

2020 Volume 230, Issue 5-6, Page(s) 339–345

Abstract: Recent large-scale studies of opsin gene contents in representatives of the largest order of insects, the Coleoptera (beetles), revealed that the blue wavelength-sensitive (B) opsin subfamily is absent in this clade, while the ultraviolet- (UV) and long ... ...

Abstract	Recent large-scale studies of opsin gene contents in representatives of the largest order of insects, the Coleoptera (beetles), revealed that the blue wavelength-sensitive (B) opsin subfamily is absent in this clade, while the ultraviolet- (UV) and long wavelength-sensitive (LW) opsin subfamilies are broadly conserved with gene duplications possibly reintroducing blue sensitivity in select subclades. Little is known yet, however, how opsin genes are expressed in the compound eyes of beetles. In a previous study, we analyzed opsin gene expression in the red flour beetle Tribolium castaneum, a member of the family of darkling beetles (Tenebrionidae), and found that a singleton LW opsin homolog is homogeneously expressed in all photoreceptors of the compound eye retina with a singleton UV opsin homolog being co-expressed in the R7 subtype photoreceptors. To probe for the evolutionary conservation of these expression patterns, we isolated complete opsin transcript sequences from three additional species in the subfamily Tenebrionidae (Tribolium confusum, Tenebrio molitor, Zophobas morio) and studied their expression via whole mount in situ hybridization in the pupal retina. These experiments revealed very similar, if not identical, photoreceptor subtype-specific expression patterns in all three species compared with T. castaneum. Documenting a deep conservation of photoreceptor subtype-specific opsin gene expression in this range of darkling beetles, our study provides a first point of reference for broader comparative studies of retinal organization in the Coleoptera.
MeSH term(s)	Animals ; Biological Evolution ; Coleoptera/genetics ; Gene Duplication ; Gene Expression ; In Situ Hybridization ; Insect Proteins/genetics ; Insect Proteins/metabolism ; Opsins/genetics ; Opsins/metabolism ; Photoreceptor Cells, Invertebrate/metabolism ; Pupa/genetics ; Pupa/metabolism ; Retina/metabolism ; Rod Opsins ; Tenebrio/genetics ; Tenebrio/metabolism ; Tribolium/genetics ; Tribolium/metabolism
Chemical Substances	Insect Proteins ; Opsins ; Rod Opsins ; long-wavelength opsin
Language	English
Publishing date	2020-10-02
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1327962-2
ISSN	1432-041X ; 0949-944X
ISSN (online)	1432-041X
ISSN	0949-944X
DOI	10.1007/s00427-020-00669-2
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