Host Immune Function Research Articles

Bacterial biofilms: novel strategies for intestinal colonization by probiotics

Probiotics can improve the microecological balance of the body and have special effects in promoting nutrient absorption, controlling intestinal infections, and regulating immune function. However, there are problems such as difficult colonization in the gastrointestinal environment and low oral bioavailability. Bacterial biofilms are organized bacterial cells that adhere to an abiotic or biotic surface and are enclosed in extracellular polymeric substances of exopolysaccharides (EPS), extracellular DNA (eDNA), proteins and lipids, with a three-dimensional spatial structure. Probiotics with the help of bacterial biofilms have obvious advantages over planktonic bacteria in stress resistance, combating pathogens and modulating the host's immune function, which provides a new research idea for the development of probiotics. This paper expounded on the advantages of probiotics with the help of bacterial biofilms, and focused on introducing substances that could promote the formation of probiotic biofilms and the mechanisms, and the safety of probiotic biofilms. Currently, research on probiotic biofilms is still in its infancy, and this paper is expected to provide references for future research in this field.

Eriocheir sinensis vesicle-associated membrane protein can enhance host cell phagocytosis to resist Spiroplasma eriocheiris infection

Vesicle-associated membrane protein (VAMP) belongs to the receptor protein on the membrane of the secretory transport vesicle and involves in host immune function. The intracellular pathogen Spiroplasma eriocheiris could cause Eriocheir sinensis tremor disease. In a previous study, it was found E. sinensis VAMP (EsVAMP) was differently expressed in S. eriocheiris infection by proteomics analysis. This study mainly aims at the function of EsVAMP in the process of the S. eriocheiris infection. The length of EsVAMP gene was 1681 bp, which contained a 395 bp open reading frame, 90 bp 5′-non-coding region (UTR) and 1277 bp 3′-UTR. The results of qPCR showed that EsVAMP was expressed highly in hemocytes and nerves, followed by gills, intestines and hepatopancreas, and lowly expressed in heart and muscles. EsVAMP in hemocytes was up-regulated after S. eriocheiris infection. After EsVAMP over-expression and S. eriocheiris infection, the RAW264.7 cell morphology and cell viability of the experiment group were significantly better than the control group. Meanwhile, the copy number of S. eriocheiris in the experiment group was significantly lower than that in the control group. After EsVAMP and pCMV-Cre-mCherry were ligated and transfected into RAW264.7 cells, it was found that EsVAMP and lysosome co-localized. Meanwhile, the phagocytosed inactivated S. eriocheiris number and phagocytosed efficiency in RAW264.7 cells were increased significantly. The interference experiment was carried out by synthesizing EsVAMP dsRNA to verify that the EsVAMP transcriptions were successfully suppressed. The S. eriocheiris copy number and the mortality of crab increased significantly after EsVAMP RNAi and S. eriocheiris infection. Meanwhile, the phagocytosed inactivated S. eriocheiris number and phagocytosed efficiency in hemocytes decreased significantly after EsVAMP RNAi and S. eriocheiris infection. These results showed that VAMP was involved in the cell phagocytosis to resist pathogen infection.

When sexual selection in hosts benefits parasites.

In host-parasite coevolution, the parasite is selected to increase its infectivity while host is selected to resist the parasite infection. It is widely held that parasite-mediated sexual selection can further amplify the selective pressure on the host to overcome parasite infection. In this paper we focus on certain types of parasites, those that can impair the activity of the host immune function to prevent signs of sickness. We show that the effect of sexual selection can actually reduce the selective pressure on the host immune response to adapt to the parasite infection. We design a simple mathematical model for a population of sexually reproducing organism in which individuals are choosy, preferring traits that are correlated negatively with immune system activity. We introduce to this population a parasite that can suppress activation of the host's immune response. Our results show that even though the host immune system is likely to ultimately evolve and adapt to the parasite infection, when sexual selection is part of this process, it can slow down this evolution on the host and give the parasite more time to get established.

Effect of calving season on metritis incidence and bacterial content of the vagina in dairy cows

Heat stress and uterine diseases, including metritis and endometritis, both reduce milk yields and reduce reproductive performance. Bacterial growth is promoted by elevated temperature while heat stress reduces host immune cell function, but it is not known whether increased environmental temperature promotes uterine disease by altering host immunity or bacterial growth. We hypothesize that seasonal variations in environmental temperature influence metritis incidence in the dairy cow independent of bacterial prevalence in the reproductive tract. To investigate how environmental temperature may impact metritis incidence, records of 3507 calvings in Florida over a 5-year period were evaluated. The incidence of metritis increased from 21.1% in the cool season (October through March) to 24.2% during the warm season (April through September, P < 0.05). To elucidate a link between environmental temperature and uterine disease, 102 cows were enrolled during the warm season (September 2017; n = 51) and cool season (February–March 2018; n = 51). Cows were maintained on pasture during the dry period and moved to free stall barns with fans and water soakers immediately prior to calving and remained in that environment after calving. Vaginal mucus was collected and scored on days 7 (to evaluate metritis) and 21 (to evaluate endometritis) postpartum to evaluate the incidence of uterine disease and quantify bacterial content and species using qPCR. Daily milk yield for the first 60 DIM was reduced during the warm season compared with the cool season (32.6 ± 1.62 vs 37.23 ± 1.60 kg, P < 0.05) consistent with effects of prepartum heat stress. Interestingly, more cows had persistent uterine disease on both d 7 and d 21 in the warm season compared with the cool season (58.0 vs 29.4%, P < 0.05). Regardless of calving season the total bacterial content in the vagina was greater on d 7 compared to d 21. While metritis incidence was increased in the warm season, the vaginal content of total bacteria, Escherichia coli, Trueperella pyogenes, Fusobacterium necrophorum and Prevotella melaninogenica were similar during the cool season and the warm season. Our data suggests that prepartum heat stress related to season of calving increased the incidence of metritis and persistence of uterine disease in the dairy cow independent of vaginal bacteria content. The possibility that prepartum heat stress perturbs host immune function and increases the risk of metritis when cows are exposed to an equivalent number of pathogenic bacteria requires further investigation.

Predictive value of Leukocyte ImmunoTest (LIT™) in cancer patients: a prospective cohort study

Early diagnosis of cancer is crucial to initiate prompt treatment for better patient outcomes. The host immune function and its associated modulators are considered to be potential biomarkers for early cancer diagnosis. Immune and immune-checkpoint biomarkers have been reported to contribute to cancer development, while a high neutrophil-to-lymphocyte ratio has been shown to be associated with poor survival outcomes in a variety of cancers. One hundred sixty-one cancer patients were recruited to take a cost-effective novel Leukocyte ImmuneTest (LIT). LIT was measured to objectively determine the pre-treatment immune status of patients. The correlation between LIT and other conventional diagnostic markers or tumor-related variables was then investigated. Significant correlations between LIT and white blood cell count, smoking status, and tumor stage 4 were found. In addition, the LIT score significantly differentiated between malignant and benign tumors in this study population. Our work raises the possibility to use LIT for general screening surveillance before further costly specialized equipment is applied for cancer diagnosis.

In-silico identification of critical residues in the mannose-transfer mechanism of phosphatidyl-myo-inositol mannosyltransferase B′

The complex cellular envelope is one of the major reasons behind the survival in hostile conditions and the emergence of the drug-resisting properties of mycobacteria. Phosphatidyl-myo-inositol hexamannoside (PIM6), Lipomannan (LM), and Lipoarabinomannan (LAM) are important structural constituents of the cell envelope and have roles in modulating host immune functions. Phosphatidyl-myo-inositol (PI) is first mannosylated at the 2-position of the inositol group by phosphatidyl-myo-inositol mannosyltransferase A (PimA) to produce phosphatidyl-myo-inositol monomannoside (PIM1). This PIM1 is then further mannosylated at the 6-position of the inositol group by phosphatidyl-myo-inositol mannosyltransferase B' (PimB′) utilizing GDP-mannose as the mannose-donor to synthesize phosphatidyl-myo-inositol dimannoside (PIM2) and GDP. Further mannosylation and acylation on PIM2 produce Ac1/2PIM4, which can then be converted to either Ac1/2PIM6 or LM/LAM. Detailed functional mechanism of how PimB′ transfers the mannose sugar to PIM1 is not understood. Using molecular docking, the interactions of PimB′ with the substrate PIM1 and the product PIM2 are analyzed here. Molecular dynamics (MD) simulations of PimB′ with the substrates and the products were performed for 300ns to find out critical residues involved in the mannose-transfer reaction. Docking and MD analyses indicated the residues R206 and R210 bind both PIM1 and PIM2 and are critical in the mannose-transfer reaction. The residues 120HEVGWSMLPGS130 and 281RTRGGGL288 were involved in the transfer of PIM1 from the active site. The residues 18IGG20, K211, E290, G291, 294IV295, and E298 were also important in the mannosylation reaction. The crucial residues obtained from this study may help design novel drugs against mycobacterial PimB'.

SY29-4 Secondary effects of radiation exposure on host immune function in cancer immunotherapy

Upon irradiation of tumor tissue, the immunogenicity of tumor cells increases and host immune function is also activated. On the other hand, as was classically known, there are certainly cases in which irradiation significantly alters the profile of immune cells in the irradiated area and negatively affects immune function. At the basic research level, the conditions under which host immune function is activated or abrogated by irradiation have gradually been clarified. Of course, the results of basic research cannot be directly applied to clinical practice, but it is also not realistic to blindly incorporate many parameters, such as irradiation dose and the order of irradiation and drug administration, into the design of clinical trials.

Seasonality of host immunity in a tropical disease system

AbstractInfectious disease systems frequently exhibit strong seasonal patterns, yet the mechanisms that underpin intra‐annual cycles are unclear, particularly in tropical regions. We hypothesized that host immune function fluctuates seasonally, contributing to oscillations in infection patterns in a tropical disease system. To test this hypothesis, we investigated a key host defense of amphibians against a lethal fungal pathogen, Batrachochytrium dendrobatidis (Bd). We integrated two field experiments in which we perturbed amphibian skin secretions, a critical host immune mechanism, in Panamanian rocket frogs (Colostethus panamansis). We found that this immunosuppressive technique of reducing skin secretions in wild frog populations increased Bd prevalence and infection intensity, indicating that this immune defense contributes to resistance to Bd in wild frog populations. We also found that the chemical composition and anti‐Bd effectiveness of frog skin secretions varied across seasons, with greater pathogen inhibition during the dry season relative to the wet season. These results suggest that the effectiveness of this host defense mechanism shifts across seasons, likely contributing to seasonal infection patterns in a lethal disease system. More broadly, our findings indicate that host immune defenses can fluctuate across seasons, even in tropical regions where temperatures are relatively stable, which advances our understanding of intra‐annual cycles of infectious disease dynamics.

Increased Virulence and Large-Scale Reduction in Genome Size of Tetraploid Candida albicans Evolved in Nematode Hosts.

Candida albicans is an opportunistic fungal pathogen of humans, yet the within-host dynamics of C. albicans infection are not clear. While C. albicans is commonly diploid, it exhibits a range of ploidies, including tetraploidy. Previous work found that tetraploid C. albicans populations exhibited rapid adaptation and significant genome instability when evolved in vitro. Host immune function alters the rate and magnitude of C. albicans virulence evolution, but the effects of the host immunity on tetraploid C. albicans populations are unclear. Here, we tested the effects of the host immunity on genome stability and virulence evolution of tetraploid C. albicans using experimental evolution. We selected for C. albicans increased virulence within either immunocompetent or immunocompromised Caenorhabditis elegans hosts. After nine passages we observed a response to selection for increased virulence. Both populations exposed to either immunocompetent or immunocompromised hosts increased virulence after passage through C. elegans hosts. However, the C. albicans populations passaged through immunocompetent hosts under selection exhibited unique temporal dynamics, a rapid increase in virulence and then subsequent loss of virulence. Most C. albicans populations exhibited genome size reduction within six passages, however populations exposed to immunocompetent hosts exhibited the most rapid transition to ~diploid. Therefore, we found that tetraploids rapidly increase in virulence and decrease genome size within host environments. Further, the combination of selection for greater virulence in the presence ofimmunocompetent hosts results in major virulence fluctuations and genome size changes. Thus, host immunity significantly impacts the evolutionary trajectories of tetraploid C. albicans.

Microbiome–Immune Interactions in Allergy and Asthma

The human microbiota has been established as a key regulator of host health, in large part owing to its constant interaction with and impact on host immunity. A range of environmental exposures spanning from the prenatal period through adulthood are known to affect the composition and molecular productivity of microbiomes across mucosal and dermal tissues with short- and long-term consequences for host immune function. Here we review recent findings in the field that provide insights into how microbial-immune interactions promote and sustain immune dysfunction associated with allergy and asthma. We consider both early life microbiome perturbation and the molecular underpinnings of immune dysfunction associated with subsequent allergy and asthma development in childhood, as well as microbiome features that relate to phenotypic attributes of allergy and asthma in older patients with established disease.

NAD-catabolizing ectoenzymes of Schistosoma mansoni.

Infection with schistosomes (blood flukes) can result in the debilitating disease schistosomiasis. These parasites survive in their host for many years, and we hypothesize that proteins on their tegumental surface, interacting with the host microenvironment, facilitate longevity. One such ectoenzyme - the nucleotide pyrophosphatase/phosphodiesterase SmNPP5 can cleave ADP (to prevent platelet aggregation) and NAD (likely preventing Treg apoptosis). A second tegumental ectoenzyme, the glycohydrolase SmNACE, also catabolizes NAD. Here, we undertake a comparative biochemical characterization of these parasite ectoenzymes. Both are GPI-linked and exhibit different optimal pH ranges. While SmNPP5 requires divalent cations, SmNACE does not. The KM values of the two enzymes for NAD at physiological pH differ: SmNPP5, KM = 340 µM ± 44; SmNACE, KM = 49 µM ± 4. NAD cleavage by each enzyme yields different products. SmNPP5 cleaves NAD to form nicotinamide mononucleotide (NMN) and AMP, whereas SmNACE cleaves NAD to generate nicotinamide (NAM) and adenosine diphosphate ribose (ADPR). Each enzyme can process the other's reaction product. Thus, SmNACE cleaves NMN (to yield NAM and ribose phosphate) and SmNPP5 cleaves ADPR (yielding AMP and ribose phosphate). Metabolomic analysis of plasma containing adult worms supports the idea that these cleavage pathways are active in vivo. We hypothesize that a primary function of SmNPP5 is to cleave NAD to control host immune cell function and a primary function of SmNACE is to cleave NMN to generate the vital nutrient nicotinamide (vitamin B3) for convenient uptake by the worms. Chemical inhibition of one or both ectoenzymes could upset worm metabolism and control schistosome infection.

Intratumoral delivery of dendritic cells plus anti-HER2 therapy triggers both robust systemic antitumor immunity and complete regression in HER2 mammary carcinoma

BackgroundHuman epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem....

Biological sex: an understudied factor driving disease susceptibility in pigs.

Biological sex is a major host factor influencing risk for infectious disease-associated mortality, and chronic inflammatory and metabolic diseases. Research in human and rodent models -has revealed sex differences that exist across organ systems during health and disease that may contribute to sex biases in disease risk. Despite the robust and growing literature on the role of sex as a risk factor in human disease, comparatively little attention has been focused on investigating the role of biological sex in disease susceptibility in agriculturally important animal populations such as the pig. To date, comparisons between sexes have focused on carcass composition, growth rate, and feed efficiency in pigs. However, there is a large gap in the literature regarding the effects of biological sex on other integral aspects of health and disease. The objective of this review is to highlight the available literature reporting sex differences in pig health and biology with an emphasis on sex differences in mortality, immunity, and gastrointestinal (GI) physiology and to address biological sex as a significant biological variable in disease risk and research study design. A basic overview of the biology of sex differences including the major hormonal and genetic/chromosomal mechanisms of sexual differentiation and the developmental periods in which sex differences emerge will be covered. This review will also discuss how production-relevant management and environmental factors (e.g., wean age, castration, stress, and nutrition) interact with biological sex to shape host immune and GI development and function. Perceived gaps in knowledge and areas of future research will also be discussed.

Edwardsiella piscicida YccA: A novel virulence factor essential to membrane integrity, mobility, host infection, and host immune response

YccA is a hydrophobic protein with seven transmembrane domains. The function of YccA is largely unknown in pathogenic bacteria. Edwardsiella piscicide (formerly known as E. tarda) is an aquatic pathogen that can infect various economically important fish, including flounder (Paralichthys olivaceus) and tilapia (Oreochromis niloticus). In this study, we investigated the role of YccA in E. piscicida by the construction of a markerless yccA in-frame mutant strain, TX01ΔyccA. We found that (i) in comparison to the wild type TX01, TX01ΔyccA exhibited markedly compromised tolerance to high temperature and tobramycin; (ii) deletion of yccA significantly impaired the integrity of the cell membrane and retarded bacterial biofilm formation and mobility; (iii) deficiency of yccA reduced bacterial adhesion and invasion of fish cells and immune tissues, while the introduction of a trans-expressed yccA gene restored the lost virulence of TX01ΔyccA; and (iv) host immune responses induced by TX01 and TX01ΔyccA were different in terms of reactive oxygen species (ROS) levels and expression levels of cytokines. Taken together, the results of our study indicate that YccA is a novel virulence factor of E. piscicida, and YccA is essential for bacterial pathogenicity through evasion of the host's innate immune functions.

Alterations in intestinal microbiota in ultramarathon runners

To date, only one study has reported changes in the gut microbiome of an ultramarathon runner before and after competing in the race. Herein we aimed to investigate changes in intestinal microbiota in nine ultramarathon runners. Eight of the nine participants ran 96.102 km (up 8062 m, down 6983 km) and one ran 99.12 km (up 8448 m, down 7369 m) within 38–44 h. Intestinal microbiota alterations were examined at three timepoints: before (Pre), after (Post), and 10 days after (Recovery) the race. The α- and β-diversity of intestinal microbiota were unaffected by the race. Six of the nine participants showed the B-type enterotype, while the remaining three showed the P-type enterotype; however, significant difference between enterotypes was not observed in the influence of the ultramarathon on intestinal microbiota. The abundance of mean Faecalibacterium prausnitzii, was significantly decreased from 2.9% (Pre) to 1.6% (Post), as well as other three butyrate producing bacteria. One participant with the largest decrease in F. prausnitzii abundance (− 85.7%) reported sluggishness and shallow sleep from Post to Recovery. Our findings revealed that the abundance of butyrate-producing bacteria is decreased in ultramarathon runners, which consequently decreases butyrate levels in the intestine and affects host immune function.

Immunomodulatory effect and histological alteration of thermally oxidized sunflower oil in male Wistar rats

Many foods are prepared by deep-frying as this provides unique flavors/textures that improve overall palatability to consumers. Sunflower oil is one of the most widely-used frying oils in the world. However, during frying, fats in the foodstuff are heated to &gt; 150° C and concurrently come into contact with agents found in the air, water, and other foods being cooked at the same time. Since long-term consumption of oxidized/oxidation products can contribute to the development of a variety of pathologies. Used cooking oil has become of increased concern to both health administrators and consumers. Few studies have sought to examine potential immunomodulatory effects from exposures to sunflower oil or its oxidized/oxidation products. To address this gap in knowledge, here, sunflower oil was used to fry potatoes at 190° C, every 30 min; a new 100 g batch of slices was cooked. Frying was performed continuously for 5h/day for 2 and 4 days (10 and 20 h total), and then the parental uncooked oil and each of the used oils were provided to Wistar rats in their diet (at 20% level) for a total of 10 weeks. Measures of body weight\food intake indicated that diets containing the used oils led to slightly reduced food intakes and host weights. Kidney weights were not affected by consumption of the two used oils, but the liver was enlarged in rats fed with the oil treated for 20 h. Evaluation of key lipid-serum parameters, i.e., total cholesterol, HDL cholesterol, and triglycerides, revealed a diet-related decrease in each; oxidized fats reduce their concentration compared to fresh fats. Conversely, serum LDL cholesterol levels were increased. Histological analyses indicated that consumption of the oxidized oils caused both kidney (e.g., tubular/glomerular dilation, vascular congestion, inflammation, tubular necrosis) and liver (e.g., vascular congestion, inflammation, necrosis) damages. Assessments of host immune function, i.e., ability to form antibody to ovalbumin (OVA) challenge, indicated that in rats fed the used oil, there were significant decreases in serum anti-OVA antibody levels. This suggested that host immunocompetence could be compromised as a result of long-term consumption of a diet containing a relatively high (i.e., 20%) content of used sunflower oils.

Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2.

The SARS-CoV-2 non-structural protein 1 (Nsp1) contains an N-terminal domain and C-terminal helices connected by a short linker region. The C-terminal helices of Nsp1 (Nsp1-C-ter) from SARS-CoV-2 bind in the mRNA entry channel of the 40S ribosomal subunit and blocks mRNA entry, thereby shutting down host protein synthesis. Nsp1 suppresses host immune function and is vital for viral replication. Hence, Nsp1 appears to be an attractive target for therapeutics. In this study, we have in silico screened Food and Drug Administration (FDA)-approved drugs against Nsp1-C-ter. Among the top hits obtained, montelukast sodium hydrate binds to Nsp1 with a binding affinity (KD) of 10.8 ± 0.2 µM in vitro. It forms a stable complex with Nsp1-C-ter in simulation runs with -95.8 ± 13.3 kJ/mol binding energy. Montelukast sodium hydrate also rescues the inhibitory effect of Nsp1 in host protein synthesis, as demonstrated by the expression of firefly luciferase reporter gene in cells. Importantly, it shows antiviral activity against SARS-CoV-2 with reduced viral replication in HEK cells expressing ACE2 and Vero-E6 cells. We, therefore, propose montelukast sodium hydrate can be used as a lead molecule to design potent inhibitors to help combat SARS-CoV-2 infection.

A176 UTILITY OF MACHINE LEARNING FOR SERUM METABOLOMIC DATA ANALYSIS IN PEDIATRIC CROHN DISEASE

BackgroundThe pathogenesis of pCD remains poorly understood, but evidence suggests roles for genetics, environment, immune response, and gut microbes. Microbial changes can contribute to chronic inflammation and correlate with disease severity. Metabolomics reflects interactions between host immune and gut microbial function by quantifying compounds in biological samples. Therefore, metabolomics provides a unique opportunity to gain insight into pCD pathogenesis.AimsTo correlate disease severity, metabolites, and clinical data by applying machine learning algorithms in pediatric Crohn Disease (pCD).MethodsImageKids is a multicenter, prospective, cohort observational study, conducted to develop magnetic resonance enterography (MRE) indices for pCD. Paired serum specimens were collected at study initiation (Visit One; V1) and completion (Visit Four; V4; 18 months) for 120 pCD patients. Serum from patients with representative clinical scenarios and paired samples was analyzed at The Metabolomics Innovation Centre (TMIC; University of Alberta) and 131 metabolites were identified. Metabolites were analyzed via Unsupervised (U.ML) and Supervised (S.ML) Machine Learning algorithms based on Scikit-learn library in Python. Principal Component Analysis (PCA) was used to identify the variation pattern of the patients’ metabolome. Classifiers and regression algorithms were trained to assess correlation with disease activity.ResultsResults were available for the 56 paired samples. U.ML demonstrated distinct metabolome profiles with V1 clustering mainly attributed to aspartic acid, glutamic acid, and kynurenine. V4 clustering was mainly attributed to spermidine, spermine, total dimethylarginine. Furthermore, demographics was found as an important environmental factor driving distinct patterns of the metabolomics profile.After training different classifiers and regressors with S. ML algorithms, metabolome data were correlated with disease severity (defined by C-reactive protein and fecal calprotectin). Isoleucine, p-hydroxyhippuric acid, and putrescine were the top three compounds associated with disease severity. The accuracy of our classification models was of 80% and the coefficient of determination of our regression models was 0.5ConclusionsMetabolomic analysis can provide insight into disease pathogenesis and help predict disease severity among pCD patients. The correlation between metabolomics and disease severity might allow a better understanding of changes in host-microbe interactions and introduce new diagnostic or therapeutic options.Funding AgenciesCIHR

Dietary Lactobacillus-Derived Exopolysaccharide Enhances Immune-Checkpoint Blockade Therapy.

Gut microbiota- and probiotic-derived metabolites are attractive agents to augment the efficacy of immunotherapies. Here we demonstrated that dietary consumption of Lactobacillus-derived exopolysaccharide induced CCR6+ CD8+ T cells in Peyer's patches and improved the tumor microenvironment to augment the therapeutic effects of immune-checkpoint blockade against CCL20-producing tumors. See related commentary by Di Luccia and Colonna, p. 1189. This article is highlighted in the In This Issue feature, p. 1171.

Abstract P4-04-10: Pharmacological targeting of cholinergic receptors as a novel breast cancer immunotherapy

Abstract There is a general consensus that the devastating effect of malignant breast cancers (MBCs) is due in part to the ability of breast tumors to exploit host immune functions by subverting normal mechanisms of immunosurveillance. For example, while immunotherapies based on immune checkpoint inhibition in lymphocytes have been associated with better prognosis in other cancers, the efficacy in breast cancer has been limited. We focus here on activating biochemical pathways in antigen-presenting dendritic cells (DCs) that are otherwise immunosuppressive to stimulate the activity of tumor-infiltrating lymphocytes through a novel mechanism. To this end, we recently discovered using an immune-competent mouse model of MBC that breast cancer cells exploit adaptive immune cells such as DCs that express CHRNA7, the α7 nicotinic acetylcholine receptor. Based on the importance of the CHRNA7 signaling pathway in the control of normal inflammation in macrophages in general, we show here that CHRNA7 stimulation in DCs leads to an activation of lymphocytes associated with a reduction in MBC. Specifically, mice lacking the CHRNA7 gene have (a) decreased survival, (b) increased tumor growth kinetics, (c) immunophenotyping revealed a reduction in the “cancer-permissive” phenotype in CHRNA7 KO mice, and (d), a commensurate reduction in T cell proliferation. Based on these mechanistic proof of principle studies, we demonstrate that in contrast to the loss of CHRNA7 in KO, pharmacological activation of CHRNA7 with AR-R17779 has the opposite effect by stimulating DCs to activate the adaptive immune response which leads to tumor progression and increased survival. These findings demonstrate the preclinical potential of AR-R17779 as a clinically relevant approach to stimulate the adaptive immune system through a novel pathway that has not been examined to date, and with a small molecule drug that is stable, specific and well-tolerated. Citation Format: Brian P. Eliceiri, Jin Qian, Sarah Blair. Pharmacological targeting of cholinergic receptors as a novel breast cancer immunotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-10.