The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages

2021 ◽  
Vol 118 (37) ◽  
pp. e2102434118
Author(s):  
Sri Murugan Poongkavithai Vadevoo ◽  
Gowri Rangaswamy Gunassekaran ◽  
ChaeEun Lee ◽  
NaHye Lee ◽  
Jiyoun Lee ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Immune Cell ◽  
Odorant Receptor ◽  
Odorant Receptors ◽  
Tumor Associated Macrophages ◽  
Immune Cell Population ◽  
Lactate Sensor ◽  
And Function ◽  
Multiple Signaling ◽  
G Protein Coupled

Expression and function of odorant receptors (ORs), which account for more than 50% of G protein–coupled receptors, are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Tumor-derived lactate plays a crucial role in multiple signaling pathways leading to generation of tumor-associated macrophages (TAMs). In this study, we hypothesized that the macrophage OR Olfr78 functions as a lactate sensor and shapes the macrophage–tumor axis. Using Olfr78+/+ and Olfr78−/− bone marrow–derived macrophages with or without exogenous Olfr78 expression, we demonstrated that Olfr78 sensed tumor-derived lactate, which was the main factor in tumor-conditioned media responsible for generation of protumoral M2-TAMs. Olfr78 functioned together with Gpr132 to mediate lactate-induced generation of protumoral M2-TAMs. In addition, syngeneic Olfr78-deficient mice exhibited reduced tumor progression and metastasis together with an increased anti- versus protumoral immune cell population. We propose that the Olfr78–lactate interaction is a therapeutic target to reduce and prevent tumor progression and metastasis.

scholarly journals The cell biology of smell

2010 ◽  
Vol 191 (3) ◽  
pp. 443-452 ◽  
Author(s):  
Shannon DeMaria ◽  
John Ngai
Keyword(s):  
Olfactory System ◽  
Cell Biology ◽  
Odorant Receptor ◽  
Large Family ◽  
G Protein Coupled Receptors ◽  
Odorant Receptors ◽  
Chemical Structures ◽  
Wide Range ◽  
G Protein Coupled ◽  
The Brain

The olfactory system detects and discriminates myriad chemical structures across a wide range of concentrations. To meet this task, the system utilizes a large family of G protein–coupled receptors—the odorant receptors—which are the chemical sensors underlying the perception of smell. Interestingly, the odorant receptors are also involved in a number of developmental decisions, including the regulation of their own expression and the patterning of the olfactory sensory neurons' synaptic connections in the brain. This review will focus on the diverse roles of the odorant receptor in the function and development of the olfactory system.

Biology of the Heparanase–Heparan Sulfate Axis and Its Role in Disease Pathogenesis

2021 ◽  
Vol 47 (03) ◽  
pp. 240-253 ◽  
Author(s):  
Israel Vlodavsky ◽  
Uri Barash ◽  
Hien M. Nguyen ◽  
Shi-Ming Yang ◽  
Neta Ilan
Keyword(s):  
Cell Proliferation ◽  
Heparan Sulfate ◽  
Cell Activation ◽  
Immune Cell ◽  
Enzyme Activation ◽  
Cell Of Origin ◽  
Immune Cell Activation ◽  
Cytokines And Chemokines ◽  
And Function ◽  
Multiple Signaling

AbstractCell surface proteoglycans are important constituents of the glycocalyx and participate in cell–cell and cell–extracellular matrix (ECM) interactions, enzyme activation and inhibition, and multiple signaling routes, thereby regulating cell proliferation, survival, adhesion, migration, and differentiation. Heparanase, the sole mammalian heparan sulfate degrading endoglycosidase, acts as an “activator” of HS proteoglycans, thus regulating tissue hemostasis. Heparanase is a multifaceted enzyme that together with heparan sulfate, primarily syndecan-1, drives signal transduction, immune cell activation, exosome formation, autophagy, and gene transcription via enzymatic and nonenzymatic activities. An important feature is the ability of heparanase to stimulate syndecan-1 shedding, thereby impacting cell behavior both locally and distally from its cell of origin. Heparanase releases a myriad of HS-bound growth factors, cytokines, and chemokines that are sequestered by heparan sulfate in the glycocalyx and ECM. Collectively, the heparan sulfate–heparanase axis plays pivotal roles in creating a permissive environment for cell proliferation, differentiation, and function, often resulting in the pathogenesis of diseases such as cancer, inflammation, endotheliitis, kidney dysfunction, tissue fibrosis, and viral infection.

scholarly journals IMMU-42. CD8+ T-CELLS MEDIATE IMMUNOEDITING, AND INFLUENCE GENOTYPE, TUMOR ONCOGENIC PATHWAYS AND MICROENVIRONMENT DURING PROGRESSION OF MURINE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi128-vi128
Author(s):  
J Robert Kane ◽  
Junfei Zhao ◽  
Takashi Tsujiuchi ◽  
Brice Laffleur ◽  
Aayushi Mahajan ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Progression ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Mapk Signaling ◽  
Tumor Evolution ◽  
Immune Recognition ◽  
Immune Cell Population ◽  
Immune Effector ◽  
Cancer Immunoediting

Abstract Cancer immunoediting shapes tumor progression by the immunological selection of tumor cell variants that can evade immune recognition. Given the immune evasive cellular diversity of glioblastoma, we hypothesized that CD8+ T-cells mediate immunoediting in this tumor. We evaluated tumor progression in the absence of CD8+ T-cells by depleting this immune cell population in a transgenic murine glioma model. Tumors generated in the absence of CD8+ T-cells developed poorly in recipients with intact immunity, implying a more immunogenic profile. These tumors demonstrated increased chromosomal instability, gene fusions, MAPK signaling, and macrophage infiltration. These observations were stochastic, suggesting variability in the mode of tumor evolution in the absence of this immune effector. MAPK activation was correlated with macrophage recruitment in two transgenic murine models and the human disease. Our results indicate that CD8+ T-cells mediate a strong immunoediting selection in glioblastoma that protect against the hallmarks of cancer and drive immune evasion.

scholarly journals Phenylboronic Acid Conjugated to Doxorubicin for the Treatment of Hepatocellular Carcinoma Through Transcatheter Arterial Chemoembolization

2021 ◽  
Author(s):  
Byung-Yoon Kang ◽  
Sung Min Kim ◽  
Wonhee Hur ◽  
Pu Reun Roh ◽  
Ji Won Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Population ◽  
Tumor Targeting ◽  
Immune Cell ◽  
Transcatheter Arterial Chemoembolization ◽  
Phenylboronic Acid ◽  
Anticancer Effect ◽  
Immune Cell Population ◽  
And Function ◽  
Arterial Chemoembolization

Abstract Background: Anticancer strategies using nanocarrier systems via the enhanced permeability and retention (EPR) effect and tumor targeting have been explored in various cancers. In previous studies, the anticancer effect of polymerized phenylboronic acid-conjugated doxorubicin (pPBA-Dox) nanocomplexes was confirmed in various cancers, and their anticancer effect and tumor targeting ability was confirmed in hepatocellular carcinoma (HCC).This study aimed to determine the anticancer effect and changes in the liver immune cell population and function after pPBA-Dox nanocomplex infusion through transcatheter arterial chemoembolization (TACE), which is a locoregional therapy (LRT), in HCC. TACE was performed in a rat liver cancer model, and the anticancer effects, immune cell populations and functional changes were confirmed after 1 week. Magnetic resonance imaging (MRI) and flow cytometry (FACS) were performed to analyze the anticancer effect and immune cell population and function. Results: In HCC, the infusion of pPBA-Dox nanocomplexes through TACE had a stronger anticancer effect than conventional doxorubicin (Dox) and it promoted the infiltration and activation of CD4+ and CD8+ T cells in the liver. Conclusions: This study provides insight into novel targeted therapies using nanocomplexes for the treatment of HCC.

scholarly journals Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Jianying Li ◽  
Chelsea Bolyard ◽  
Gang Xin ◽  
Zihai Li
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Metabolic Pathways ◽  
Cell Function ◽  
Immune Cell ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Immune Cell Population ◽  
And Function ◽  
Cancer Immunotherapies

Tumor-infiltrating myeloid cells are a prominent pro-tumorigenic immune cell population that limit host anti-tumor immunity and present a significant obstacle for many cancer immunotherapies. Targeting the mechanisms regulating myeloid cell function within the tumor microenvironment may overcome immunotherapy resistance in some cancers. Recent discoveries in the emerging field of immunometabolism reveal that the metabolic profiles of intratumoral myeloid cells are rewired to adapt to the nutrition-limited tumor microenvironment, and this shapes their pro-tumor phenotypes. Interestingly, metabolic modulation can shift these myeloid cells toward the immune-stimulating anti-tumor phenotype. In this review, we will highlight the roles of specific metabolic pathways in the activation and function of myeloid cells, and discuss the therapeutic value of metabolically reprogramming myeloid cells to augment and improve outcomes with cancer immunotherapy.

scholarly journals 16 Long-term immune and metabolic consequences of a disrupted early life microbiota

2019 ◽  
Vol 97 (Supplement_2) ◽  
pp. 9-9
Author(s):  
Benjamin P Willing
Keyword(s):  
Early Life ◽  
Immune Cell ◽  
Antibiotic Use ◽  
Rapid Expansion ◽  
Intestinal Lumen ◽  
Immune Cell Population ◽  
Subsequent Performance ◽  
Long Term Impact ◽  
And Function

Abstract In the first weeks of life, the gastrointestinal tract changes dramatically in structure and function, including a rapid expansion and maturation of the immune cell population. Successful intestinal development comes at a significant energy cost yet is essential to subsequent performance and health. Many of the developmental changes in intestinal and immune development are dependent on the abundant and diverse population of microbes (microbiota) residing at the mucosal surface and in the intestinal lumen. We are now beginning to understand that the nature of the first exposures in the first days to weeks of life have a long-term impact on physiological processes important to metabolic health, as well as immune programming that impacts response to pathogen challenge. In this presentation I will discuss our key findings on the significant impacts early life microbial disruption have on intestinal, pancreatic, and immune function of the piglet. I will also discuss the consequences of excessive hygiene on disease resilience as well as the ability to mount a successful immune response in response to vaccination. Understanding the ability of the early life microbiota to program subsequent health provides a significant opportunity to support healthy pig production as we move away from antibiotic use in livestock production.

scholarly journals Spontaneous and sensory-evoked activity in mouse olfactory sensory neurons with defined odorant receptors

2013 ◽  
Vol 110 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Timothy Connelly ◽  
Agnes Savigner ◽  
Minghong Ma
Keyword(s):  
Spontaneous Activity ◽  
Odorant Receptor ◽  
Odorant Receptors ◽  
Spontaneous Firing ◽  
Basal Activity ◽  
Evoked Activity ◽  
Sensory Evoked ◽  
Noisy Background ◽  
G Protein Coupled ◽  
Spontaneous Firing Rate

Sensory systems need to tease out stimulation-evoked activity against a noisy background. In the olfactory system, the odor response profile of an olfactory sensory neuron (OSN) is dependent on the type of odorant receptor it expresses. OSNs also exhibit spontaneous activity, which plays a role in establishing proper synaptic connections and may also increase the sensitivity of the cells. However, where the spontaneous activity originates and whether it informs sensory-evoked activity remain unclear. We addressed these questions by examining patch-clamp recordings of genetically labeled mouse OSNs with defined odorant receptors in intact olfactory epithelia. We show that OSNs expressing different odorant receptors had significantly different rates of basal activity. Additionally, OSNs expressing an inactive mutant I7 receptor completely lacked spontaneous activity, despite being able to fire action potentials in response to current injection. This finding strongly suggests that the spontaneous firing of an OSN originates from the spontaneous activation of its G protein-coupled odorant receptor. Moreover, OSNs expressing the same receptor displayed considerable variation in their spontaneous activity, and the variation was broadened upon odor stimulation. Interestingly, there is no significant correlation between the spontaneous and sensory-evoked activity in these neurons. This study reveals that the odorant receptor type determines the spontaneous firing rate of OSNs, but the basal activity does not correlate with the activity induced by near-saturated odor stimulation. The implications of these findings on olfactory information processing are discussed.

scholarly journals Differential Kat3 Usage Orchestrates the Integration of Cellular Metabolism with Differentiation

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5884
Author(s):  
Xiaohui Hu ◽  
Masaya Ono ◽  
Nyam-Osor Chimge ◽  
Keisuke Chosa ◽  
Cu Nguyen ◽  
...  
Keyword(s):  
Cell Biology ◽  
Immune Cell ◽  
Wnt Signaling Pathway ◽  
Cellular Metabolism ◽  
Signaling Cascades ◽  
Evolutionarily Conserved ◽  
And Migration ◽  
Nuclear Receptor Family ◽  
And Function ◽  
Multiple Signaling

The integration of cellular status with metabolism is critically important and the coupling of energy production and cellular function is highly evolutionarily conserved. This has been demonstrated in stem cell biology, organismal, cellular and tissue differentiation and in immune cell biology. However, a molecular mechanism delineating how cells coordinate and couple metabolism with transcription as they navigate quiescence, growth, proliferation, differentiation and migration remains in its infancy. The extreme N-termini of the Kat3 coactivator family members, CBP and p300, by far the least homologous regions with only 66% identity, interact with members of the nuclear receptor family, interferon activated Stat1 and transcriptionally competent β-catenin, a critical component of the Wnt signaling pathway. We now wish to report based on multiomic and functional investigations, utilizing p300 knockdown, N-terminal p300 edited and p300 S89A edited cell lines and p300 S89A knockin mice, that the N-termini of the Kat3 coactivators provide a highly evolutionarily conserved hub to integrate multiple signaling cascades to coordinate cellular metabolism with the regulation of cellular status and function.

Maternal High-Fat Diet Persistently Alters Bone Marrow Immune Cell Proportions and Function in a Nonhuman Primate Model

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 222-OR
Author(s):  
MICHAEL J. NASH ◽  
TAYLOR K. SODERBORG ◽  
RACHEL C. JANSSEN ◽  
ERIC M. PIETRAS ◽  
JACOB E. FRIEDMAN
Keyword(s):  
Bone Marrow ◽  
Nonhuman Primate ◽  
High Fat Diet ◽  
Immune Cell ◽  
High Fat ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
And Function

Recent Advances of Small Molecular Regulators Targeting G Protein- Coupled Receptors Family for Oncology Immunotherapy

2019 ◽  
Vol 19 (16) ◽  
pp. 1464-1483 ◽  
Author(s):  
Peng He ◽  
Wenbo Zhou ◽  
Mingyao Liu ◽  
Yihua Chen
Keyword(s):  
G Protein ◽  
Cell Biology ◽  
Immune Cell ◽  
G Protein Coupled Receptors ◽  
Treatment Modalities ◽  
Immune Checkpoints ◽  
Considerable Proportion ◽  
Prostaglandin E ◽  
Recent Advances ◽  
G Protein Coupled

The great clinical success of chimeric antigen receptor T cell (CAR-T) and PD-1/PDL-1 inhibitor therapies suggests the drawing of a cancer immunotherapy age. However, a considerable proportion of cancer patients currently receive little benefit from these treatment modalities, indicating that multiple immunosuppressive mechanisms exist in the tumor microenvironment. In this review, we mainly discuss recent advances in small molecular regulators targeting G Protein-Coupled Receptors (GPCRs) that are associated with oncology immunomodulation, including chemokine receptors, purinergic receptors, prostaglandin E receptor EP4 and opioid receptors. Moreover, we outline how they affect tumor immunity and neoplasia by regulating immune cell recruitment and modulating tumor stromal cell biology. We also summarize the data from recent clinical advances in small molecular regulators targeting these GPCRs, in combination with immune checkpoints blockers, such as PD-1/PDL-1 and CTLA4 inhibitors, for cancer treatments.

Sign in / Sign up

Export Citation Format

Share Document