The expanding role for small molecules in immuno-oncology

Offringa, Rienk; Kötzner, Lisa; Huck, Bayard R.; Urbahns, Klaus

doi:10.1038/s41573-022-00538-9

Cited by 65 publications

(48 citation statements)

References 179 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The KYN pathway is the main direction of tryptophan catabolism, which consumes about 90% of tryptophan ( Cervenka et al., 2017 ). However, previous studies found that metabolites produced along the KYN pathway can help tumors escape immune surveillance and promote their development ( Offringa et al., 2022 ). Tryptophan can be metabolized by microorganisms into a variety of indole derivatives, which the host is unable to produce.…”

Section: Introductionmentioning

confidence: 99%

Uncovering the specificity and predictability of tryptophan metabolism in lactic acid bacteria with genomics and metabolomics

Pan

Pei

Fang

et al. 2023

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Tryptophan is metabolized by microorganisms into various indole derivatives that have been proven to alleviate diseases and promote human health. Lactic acid bacteria (LAB) are a broad microbial concept, some of which have been developed as probiotics. However, the capacity of most LAB to metabolize tryptophan is unknown. In this study, the aim is to reveal the rule of tryptophan metabolism in LAB by multi-omics. The findings showed that LAB were rich in genes for tryptophan catabolism and that multiple genes were shared among LAB species. Although the number of their homologous sequences was different, they could still form the same metabolic enzyme system. The metabolomic analysis revealed that LAB were capable of producing a variety of metabolites. Strains belonging to the same species can produce the same metabolites and have similar yields. A few strains showed strain-specificity in the production of indole-3-lactic acid (ILA), indole-3-acetic acid, and 3-indolealdehyde (IAld). In the genotype-phenotype association analysis, the metabolites of LAB were found to be highly consistent with the outcomes of gene prediction, particularly ILA, indole-3-propionic acid, and indole-3-pyruvic acid. The overall prediction accuracy was more than 87% on average, which indicated the predictability of tryptophan metabolites of LAB. Additionally, genes influenced the concentration of metabolites. The levels of ILA and IAld were significantly correlated with the numbers of aromatic amino acid aminotransferase and amidase, respectively. The unique indolelactate dehydrogenase in Ligilactobacillus salivarius was the primary factor contributing to its large production of ILA. In summary, we demonstrated the gene distribution and production level of tryptophan metabolism in LAB and explored the correlation between genes and phenotypes. The predictability and specificity of the tryptophan metabolites in LAB were proven. These results provide a novel genomic method for the discovery of LAB with tryptophan metabolism potential and offer experimental data for probiotics that produce specific tryptophan metabolites.

show abstract

Section: Introductionmentioning

confidence: 99%

Uncovering the specificity and predictability of tryptophan metabolism in lactic acid bacteria with genomics and metabolomics

Pan

Pei

Fang

et al. 2023

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…However, most patients receiving these therapies, even in combination, do not derive clinical benefit ( 1 ). Further development of agents, including small molecules ( 2 ), and strategies targeting additional immune checkpoints is critical.…”

Section: Introductionmentioning

confidence: 99%

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy

Chen

et al. 2023

Sci. Adv.

View full text Add to dashboard Cite

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8 + T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti–PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1 -deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell–based immunotherapy.

show abstract

“…Finally, it must be emphasized that, due to the increasing number of studies showing the importance of h-ecto-5′-NT as a biological target for many human diseases, − ,− a deeper comprehension of structural aspects related to its dynamic behavior is of major importance. It should be stressed that most of the studies reported so far in the literature are focused on the dynamics of bacterial 5′-NT. − To the best of our knowledge, our study is pioneering in using unbiased MD simulations for an in-depth analysis of the structural flexibility of the human homologous enzyme, h-ecto-5′-NT.…”

Section: Concluding Discussionmentioning

confidence: 99%

“…Moreover, the expression of h-ecto-5′-NT is found to be upregulated in a variety of solid tumors and blood cancer cells . Adenosine generated by overexpressed h-ecto-5′-NT accumulates in the tumor microenvironment, where it activates immunosuppressive pathways that favor the development of neoplasia. − Accumulated adenosine can also regulate angiogenesis and proliferation, migration, differentiation, and apoptosis of parenchymal cancer cells, contributing to tumor progression and metastasis. − The effects of h-ecto-5′-NT overexpression in tumorigenesis and its role in tumor immune escape and tumor metastasis have been shown in vivo . − In addition to its participation in tumor progression, h-ecto-5′-NT plays a central role in the course of several pathophysiological events and diseases, including inflammation and autoimmune, infectious, and neurological diseases. , Therefore, h-ecto-5′-NT has been recognized as a well-established biological target for cancer therapy and for the treatment of many other diseases. Several h-ecto-5′-NT inhibitors have been reported so far, ,− some of which are currently being tested in clinical trials. , Nevertheless, as discussed in the literature, ,, many of the known inhibitors have physicochemical and/or pharmacological characteristics that limit their applicability as drug candidates, such as low inhibitory potency, poor water solubility, and lack of selectivity.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of the Human Ecto-5′-Nucleotidase (h-ecto-5′-NT, CD73): Insights into Protein Flexibility and Binding Site Dynamics

Viviani

Kokh

Wade

et al. 2023

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Human ecto-5′-nucleotidase (h-ecto-5′-NT, CD73) is a homodimeric Zn 2+ -binding metallophosphoesterase that hydrolyzes adenosine 5′-monophosphate (5′-AMP) to adenosine and phosphate. h-Ecto-5′-NT is a key enzyme in purinergic signaling pathways and has been recognized as a promising biological target for several diseases, including cancer and inflammatory, infectious, and autoimmune diseases. Despite its importance as a biological target, little is known about h-ecto-5′-NT dynamics, which poses a considerable challenge to the design of inhibitors of this target enzyme. Here, to explore h-ecto-5′-NT flexibility, all-atom unbiased molecular dynamics (MD) simulations were performed. Remarkable differences in the dynamics of the open (catalytically inactive) and closed (catalytically active) conformations of the apo-h-ecto-5′-NT were observed during the simulations, and the nucleotide analogue inhibitor AMPCP was shown to stabilize the protein structure in the closed conformation. Our results suggest that the large and complex domain motion that enables the h-ecto-5′-NT open/closed conformational switch is slow, and therefore, it could not be completely captured within the time scale of our simulations. Nonetheless, we were able to explore the faster dynamics of the h-ecto-5′-NT substrate binding site, which is mainly located at the C-terminal domain and well conserved among the protein's open and closed conformations. Using the TRAPP ("Transient Pockets in Proteins") approach, we identified transient subpockets close to the substrate binding site. Finally, conformational states of the substrate binding site with higher druggability scores than the crystal structure were identified. In summary, our study provides valuable insights into h-ecto-5′-NT structural flexibility, which can guide the structure-based design of novel h-ecto-5′-NT inhibitors.

show abstract

The expanding role for small molecules in immuno-oncology

Cited by 65 publications

References 179 publications

Uncovering the specificity and predictability of tryptophan metabolism in lactic acid bacteria with genomics and metabolomics

Uncovering the specificity and predictability of tryptophan metabolism in lactic acid bacteria with genomics and metabolomics

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy

Molecular Dynamics Simulations of the Human Ecto-5′-Nucleotidase (h-ecto-5′-NT, CD73): Insights into Protein Flexibility and Binding Site Dynamics

Contact Info

Product

Resources

About