Regulation Of Immune Cell Function Research Articles

Contributions of Non-Neuronal Cholinergic Systems to the Regulation of Immune Cell Function, Highlighting the Role of α7 Nicotinic Acetylcholine Receptors.

Loewi's discovery of acetylcholine (ACh) release from the frog vagus nerve and the discovery by Dale and Dudley of ACh in ox spleen led to the demonstration of chemical transmission of nerve impulses. ACh is now well-known to function as a neurotransmitter. However, advances in the techniques for ACh detection have led to its discovery in many lifeforms lacking a nervous system, including eubacteria, archaea, fungi, and plants. Notably, mRNAs encoding choline acetyltransferase and muscarinic and nicotinic ACh receptors (nAChRs) have been found in uninnervated mammalian cells, including immune cells, keratinocytes, vascular endothelial cells, cardiac myocytes, respiratory, and digestive epithelial cells. It thus appears that non-neuronal cholinergic systems are expressed in a variety of mammalian cells, and that ACh should now be recognized not only as a neurotransmitter, but also as a local regulator of non-neuronal cholinergic systems. Here, we discuss the role of non-neuronal cholinergic systems, with a focus on immune cells. A current focus of much research on non-neuronal cholinergic systems in immune cells is α7 nAChRs, as these receptors expressed on macrophages and T cells are involved in regulating inflammatory and immune responses. This makes α7 nAChRs an attractive potential therapeutic target.

Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor

The cannabinoid-type 2 receptor (CB2R), a G protein-coupled receptor (GPCR), is an important regulator of immune cell function and a promising target to treat chronic inflammation and fibrosis. While CB2R is typically targeted by small molecules, including endo-, phyto- and synthetic cannabinoids, peptides - owing to their size - may offer a different interaction space to facilitate differential interactions with the receptor. Here we explore plant-derived cyclic cystine-knot peptides as ligands of the CB2R. Cyclotides are known for their exceptional biochemical stability. Recently they gained attention as GPCR modulators and as templates for designing peptide ligands with improved pharmacokinetic properties over linear peptides. Cyclotide-based ligands for CB2R were profiled based on a peptide-enriched extract library comprising nine plants. Employing pharmacology-guided fractionation and peptidomics we identified cyclotide vodo-C1 from sweet violet (Viola odorata) as a full agonist of CB2R with an affinity (Ki) of 1μM and a potency (EC50) of 8μM. Leveraging deep learning networks we verified the structural topology of vodo-C1 and modelled its molecular volume in comparison to the CB2R ligand binding pocket. In a fragment-based approach we designed and characterized vodo-C1-based bicyclic peptides (vBCL1-4), aiming to reduce size and improve potency. Opposite to vodo-C1, the vBCL peptides lacked the ability to activate the receptor but acted as negative allosteric modulators or neutral antagonists of CB2R. This study introduces a macrocyclic peptide phytocannabinoid, which served as template for the development of synthetic CB2R peptide modulators. These findings offer opportunities for future peptide-based probe and drug development at cannabinoid receptors.

MicroRNA-7 deficiency ameliorates d-galactose-induced aging in mice by regulating senescence of Kupffer cells.

Aging is intricately linked to immune system dysfunction. Recent studies have highlighted the biological function of microRNA-7 (miR-7) as a novel regulator of immune cell function and related diseases. However, the potential role of miR-7 in aging remains unexplored. Here, we investigated the contribution of miR-7 to d-gal-induced aging in mice, focusing on its regulation of senescent Kupffer cells. Our findings revealed that miR-7 deficiency significantly ameliorated the aging process, characterized by enhanced CD4+ T-cell activation. However, the adoptive transfer of miR-7-deficient CD4+ T cells failed to improve the age-related phenotype. Further analysis showed that miR-7 deficiency significantly reduced IL-1β production in liver tissue, and inhibiting IL-1β invivo slowed down the aging process in mice. Notably, IL-1β is mainly produced by senescent Kupffer cells in the liver tissue of aging mice, and miR-7 expression was significantly up-regulated in these cells. Mechanistically, KLF4, a target of miR-7, was down-regulated in senescent Kupffer cells in aging mouse model. Furthermore, miR-7 deficiency also modulated the NF-κB activation and IL-1β production in senescent Kupffer cells through KLF4. In conclusion, our findings unveil the role of miR-7 in d-gal-induced aging in mice, highlighting its regulation of KLF4/NF-κB/IL-1β pathways in senescent Kupffer cells. This research may enhance our understanding of miRNA-based aging immune cells and offer new avenues for new intervention strategies in aging process.

Inflammation in obsessive-compulsive disorder: A literature review and hypothesis-based potential of transcranial photobiomodulation.

Obsessive-compulsive disorder (OCD) is a disabling neuropsychiatric disorder that affects about 2%-3% of the global population. Despite the availability of several treatments, many patients with OCD do not respond adequately, highlighting the need for new therapeutic approaches. Recent studies have associated various inflammatory processes with the pathogenesis of OCD, including alterations in peripheral immune cells, alterations in cytokine levels, and neuroinflammation. These findings suggest that inflammation could be a promising target for intervention. Transcranial photobiomodulation (t-PBM) with near-infrared light is a noninvasive neuromodulation technique that has shown potential for several neuropsychiatric disorders. However, its efficacy in OCD remains to be fully explored. This study aimed to review the literature on inflammation in OCD, detailing associations with T-cell populations, monocytes, NLRP3 inflammasome components, microglial activation, and elevated proinflammatory cytokines such as TNF-α, CRP, IL-1β, and IL-6. We also examined the hypothesis-based potential of t-PBM in targeting these inflammatory pathways of OCD, focusing on mechanisms such as modulation of oxidative stress, regulation of immune cell function, reduction of proinflammatory cytokine levels, deactivation of neurotoxic microglia, and upregulation of BDNF gene expression. Our review suggests that t-PBM could be a promising, noninvasive intervention for OCD, with the potential to modulate underlying inflammatory processes. Future research should focus on randomized clinical trials to assess t-PBM's efficacy and optimal treatment parameters in OCD. Biomarker analyses and neuroimaging studies will be important in understanding the relationship between inflammatory modulation and OCD symptom improvement following t-PBM sessions.

A Comprehensive Review of the Immunomodulatory Effects of Vitamin D in Sepsis.

Sepsis remains a critical global health challenge characterised by a dysregulated immune response to infection, leading to systemic inflammation and organ dysfunction. This review examines the immunomodulatory effects of Vitamin D in sepsis, focusing on its regulation of immune cell function, modulation of cytokine production, and enhancement of antimicrobial responses. While the potential of Vitamin D as an adjunctive therapy in sepsis management is evident, challenges such as variability in Vitamin D status, uncertainties regarding optimal dosages and patient heterogeneity, and potential adverse effects require careful consideration. The review highlights the implications for future research and clinical practice, emphasising the need for standardised measurement protocols, elucidation of optimal supplementation strategies, and integration of Vitamin D assessments into routine care. Despite the complexities, Vitamin D emerges as a promising avenue for personalised interventions in sepsis, necessitating ongoing research collaboration and evidence-based guidelines to harness its full therapeutic potential and improve clinical outcomes.

Bcl-3 regulates T cell function through energy metabolism

BackgroundBcl-3 is a member of the IκB protein family and an essential modulator of NF-κB activity. It is well established that Bcl-3 is critical for the normal development, survival and differentiation of adaptive immune cells, especially T cells. However, the regulation of immune cell function by Bcl-3 through metabolic pathways has rarely been studied.ResultsIn this study, we explored the role of Bcl-3 in the metabolism and function of T cells via the mTOR pathway. We verified that the proliferation of Bcl-3-deficient Jurkat T cells was inhibited, but their activation was promoted, and Bcl-3 depletion regulated cellular energy metabolism by reducing intracellular ATP and ROS production levels and mitochondrial membrane potential. Bcl-3 also regulates cellular energy metabolism in naive CD4+ T cells. In addition, the knockout of Bcl-3 altered the expression of mTOR, Akt, and Raptor, which are metabolism-related genes, in Jurkat cells.ConclusionsThis finding indicates that Bcl-3 may mediate the energy metabolism of T cells through the mTOR pathway, thereby affecting their function. Overall, we provide novel insights into the regulatory role of Bcl-3 in T-cell energy metabolism for the prevention and treatment of immune diseases.

Modulation of Monocyte Response by MicroRNA-15b/106a/374a During Antibody-mediated Rejection in Kidney Transplantation.

Increasing evidence suggest that microRNAs are involved in the physiopathology of acute or chronic renal disease. In kidney transplantation, as key regulators of cellular homeostasis, microRNAs may be involved in the regulation of immune cell function and the allograft response. Here, we investigated the change in circulating microRNA expression profile and their involvement in the profound transcriptional changes associated with antibody-mediated rejection (AMR). Blood samples were collected at the time of the 710 kidney allograft biopsies at 4 European transplant centers. Messenger RNA and microRNA profiling analyses were performed in a discovery-to-validation study within 3 independent cohorts encompassing N = 126, N = 135, and N = 416 patients, respectively. Compared with samples with no AMR, 14 microRNAs were significantly decreased in AMR samples. Among them, expression levels of microRNA-15b, microRNA-106a, and microRNA-374a gradually decreased with the severity of AMR lesions. From their in silico-predicted target genes, a high proportion proved to be significantly upregulated in the paired transcriptomic analysis. Gene ontology analyses of microRNA-15b/-106a/-374a suggested enrichment in myeloid-related pathways, which was further refined by in silico and ex vivo transcriptomic analyses, showing a specific origin from classical CD14 + monocytes. Finally, human CD14 + monocytes were subjected to transduction by antago-microRNAs to mimic AMR pathology. MicroRNA-15b/-106a/-374a impairment resulted in cellular activation with an increased expression of CD69, CRIM1, IPO7, and CAAP1, direct and common targets of the 3 microRNAs. Together, our data provide new insights into circulating microRNAs as markers and key players in AMR, and they suggest monocyte involvement in this process.

Abstract 2908: TIGIT knockout enhances anti-tumor response of Natural Killer cells and prevents fratricide when combined with therapeutic ADCC-competent TIGIT antibodies

Abstract In this study we propose knockout of the inhibitory receptor TIGIT on Natural Killer (NK) cells enhances their anti-tumor response and prevents NK cell fratricide when combined with ADCC-competent antibodies targeting TIGIT. T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a major inhibitory receptor of both T cells and NK cells and is an emerging target for immune checkpoint blockade for the treatment of cancer. Although preclinical studies using combinations of anti-TIGIT and anti-PD-(L)1 showed promising results, the phase III SKYSCRAPER-01 trial using the combination of tiragolumab and atezolizumab for NSCLC did not meet its co-primary endpoint of progression free survival (PFS) while the overall survival (OS) at the time of this publication was immature with the study still ongoing. There is critical need to further understand the mechanism of function of TIGIT on immune cells to support its clinical use. Most of the current understanding of TIGIT regulation of immune cell function has been based on T cells, despite comparable or higher TIGIT expression on NK cells. Recent murine studies have shown the therapeutic efficacy of PD-1 and TIGIT blockade depended on the presence of NK cells, indicating they are an important immune population to consider in the efficacy of TIGIT blockade treatments. Furthermore, the majority of TIGIT antibodies have a humanized IgG, which binds to Fc receptors (CD16) and induces antibody-dependent cellular cytotoxicity (ADCC), a major contributor to their efficacy. Since both CD16 and TIGIT are highly expressed on activated NK cells, there is a potential for ADCC-driven fratricide of TIGIT+ NK cells with ADCC-competent anti-TIGIT. In this study, TIGIT knockout was performed in ex vivo-expanded primary human NK cells and anti-tumor response measured. Compared to WT NK cells, TIGIT knockout NK cells had improved in vitro killing of 3D lung cancer spheroids and increased ADCC when combined with cetuximab. TIGIT KO NK cells had upregulated mTORC1 signaling, increased basal glycolytic rate, and increased degranulation. Moreover, fratricide of WT NK cells was observed in the presence of ADCC-competent anti-TIGIT and could be ameliorated by TIGIT knockout. Altogether, this study demonstrated that the highly cytotoxic fratricide resistant TIGIT knockout NK cells have translation potential alone or in combination with ADCC-competent anti-TIGIT antibodies to enhance the efficacy of anti-TIGIT therapeutics. Citation Format: Md Faqrul Hasan, Tayler J. Croom-Perez, Jeremiah L. Oyer, Liza D. Robles-Carrillo, Thomas A. Dieffenthaller, Alicja J. Copik. TIGIT knockout enhances anti-tumor response of Natural Killer cells and prevents fratricide when combined with therapeutic ADCC-competent TIGIT antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2908.

Abstract 1840: Methylmalonic acid accumulation suppresses CD8+ T cell activation and contributes to age-induced immunosuppression

Abstract Deregulation of cytotoxic CD8+ T cells is a feature of the aging process with important consequences for anti-tumor immunity and consequently affects tumor initiation, progression, and response to immunotherapies. However, our understanding of how the aging process affects CD8+ T cells remains incomplete. Vitamin B12 deficiency is also a feature of old age caused by a well-recognized decrease in vitamin absorption. Interestingly, clinical studies have reported a significant decline in CD8+ T cells in individuals with vitamin B12 deficiency, suggesting that vitamin B12 levels might be a mechanistic link between aging and deregulation of CD8+ T cells. An important and often overlooked consequence of vitamin B12 deficiency is an elevation of methylmalonic acid (MMA) in circulation. Our laboratory has previously established a critical role for age-induced MMA in promoting progression into metastatic disease of breast and lung cancers, which coincided with a robust immunosuppressive signature. Here, we demonstrate that exposure of CD8+ T cells to MMA or culture of CD8+ T cells in the absence of vitamin B12 reduces T cell activation, thereby decreasing T cell numbers and effector function. Conversely, supplementation of vitamin B12 on CD8+ T cells isolated from old mice enhances their ability to activate and increases T cell numbers. Evaluation of the effects of MMA on the CD8+ T cells metabolome revealed a decrease in antioxidant levels, including a pronounced reduction in vitamin C and reduced glutathione, which were accompanied by an increase in both superoxide and hydrogen peroxide, suggesting that an increase in reactive oxygen species might be the link between MMA and CD8+ T cell dysfunction. Together, these results put forward the idea that MMA is an important regulator of immune cell function and that supplementation of vitamin B12 in older people and individuals diagnosed with vitamin B12 deficiency may function as an important strategy to improve immune cytotoxic responses and thereby increase anti-cancer immunosurveillance and the effectiveness of certain immunotherapies. Citation Format: Joanne D. Tejero, Stanislav Drapela, Juan Fernandez-Garcia, Sarah-Maria Fendt, Didem Ilter, Ana P. Gomes. Methylmalonic acid accumulation suppresses CD8+ T cell activation and contributes to age-induced immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1840.

Integrating single-cell RNA-seq and bulk RNA-seq to construct prognostic signatures to explore the role of glutamine metabolism in breast cancer.

Although breast cancer (BC) treatment has entered the era of precision therapy, the prognosis is good in the case of comprehensive multimodal treatment such as neoadjuvant, endocrine, and targeted therapy. However, due to its high heterogeneity, some patients still cannot benefit from conventional treatment and have poor survival prognoses. Amino acids and their metabolites affect tumor development, alter the tumor microenvironment, play an increasingly obvious role in immune response and regulation of immune cell function, and are involved in acquired and innate immune regulation; therefore, amino acid metabolism is receiving increasing attention. Based on public datasets, we carried out a comprehensive transcriptome and single-cell sequencing investigation. Then we used 2.5 Weighted Co-Expression Network Analysis (WGCNA) and Cox to evaluate glutamine metabolism-related genes (GRGs) in BC and constructed a prognostic model for BC patients. Finally, the expression and function of the signature key gene SNX3 were examined by in vitro experiments. In this study, we constituted a risk signature to predict overall survival (OS) in BC patients by glutamine-related genes. According to our risk signature, BC patients can obtain a Prognostic Risk Signature (PRS), and the response to immunotherapy can be further stratified according to PRS. Compared with traditional clinicopathological features, PRS demonstrated robust prognostic power and accurate survival prediction. In addition, altered pathways and mutational patterns were analyzed in PRS subgroups. Our study sheds some light on the immune status of BC. In in vitro experiments, the knockdown of SNX3, an essential gene in the signature, resulted in a dramatic reduction in proliferation, invasion, and migration of MDA-MB-231 and MCF-7 cell lines. We established a brand-new PRS consisting of genes associated with glutamine metabolism. It expands unique ideas for the diagnosis, treatment, and prognosis of BC.

The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy.

Epigenetic modifications may alter the proliferation and differentiation of normal cells, leading to malignant transformation. They can also affect normal stimulation, activation, and abnormal function of immune cells in the tissue microenvironment. Histone methylation, coordinated by histone methylase and histone demethylase to stabilize transcription levels in the promoter area, is one of the most common types of epigenetic alteration, which gained increasing interest. It can modify gene transcription through chromatin structure and affect cell fate, at the transcriptome or protein level. According to recent research, histone methylation modification can regulate tumor and immune cells affecting anti-tumor immune response. Consequently, it is critical to have a thorough grasp of the role of methylation function in cancer treatment. In this review, we discussed recent data on the mechanisms of histone methylation on factors associated with immune resistance of tumor cells and regulation of immune cell function.

Long non-coding RNAs: The modulators of innate and adaptive immune cells.

Before very sensitive current genomics platforms were discovered, long non-coding RNAs (lncRNAs) as controllers of gene expression, were thought to be accumulated genetic garbage. The past few years have seen a lot of interest in a large classification of non-coding transcripts with an indeterminate length of more than 200 nucleotides [1]. lncRNAs' association with immunity and disease progression has been revealed by a growing body of experimental research. Only a limited subset of lncRNAs, however, has solid proof of their role. It is also clear that various immune cells express lncRNAs differently. In this review, we concentrated on the role of lncRNA expression in the regulation of immune cell function and response to pathological conditions in macrophages, dendritic cells, natural killer (NK) cells, neutrophils, Myeloid-derived suppressor cells (MDSCs), T cells, and B cells. The innate and adaptive immune response systems may be significantly regulated by lncRNAs, according to emerging research. To discover possible therapeutic targets for the therapy of different diseases, it may be helpful to have a better realization of the molecular mechanisms beyond the role of lncRNAs in the immune response. Therefore, it is crucial to investigate lncRNA expression and comprehend its significance for the immune system.

Triclosan Reprograms Immunometabolism and Activates the Inflammasome in Human Macrophages.

To gather enough energy to respond to harmful stimuli, most immune cells quickly shift their metabolic profile. This process of immunometabolism plays a critical role in the regulation of immune cell function. Triclosan, a synthetic antibacterial component present in a wide range of consumer items, has been shown to cause immunotoxicity in a number of organisms. However, it is unclear whether and how triclosan impacts immunometabolism. Here, human macrophages were used as model cells to explore the modulatory effect of triclosan on immunometabolism. Untargeted metabolomics using integrated liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) revealed that triclosan changed the global metabolic profile of macrophages. Furthermore, Seahorse energy analysis and 13C isotope-based metabolic flux analysis revealed that triclosan decreased mitochondrial respiratory activity and promoted a metabolic transition from oxidative phosphorylation to glycolysis. Triclosan also polarizes macrophages to the proinflammatory M1 phenotype and activates the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing receptor 3 (NLRP3) inflammasome, which is consistent with triclosan-induced metabolic phenotypic modifications. Collectively, these findings showed that triclosan exposure at micromolar concentrations caused metabolic reprogramming in macrophages, which triggered an inflammatory response. These findings are important for understanding the immunotoxicity caused by triclosan, which is necessary for determining the risk posed by triclosan in the environment.

Emerging Roles of the Unique Molecular Chaperone Cosmc in the Regulation of Health and Disease.

The core-1 β1-3galactosyltransferase-specific chaperone 1 (Cosmc) is a unique molecular chaperone of core-1 β1-3galactosyltransferase(C1GALT1), which typically functions inside the endoplasmic reticulum (ER). Cosmc helps C1GALT1 to fold correctly and maintain activity. It also participates in the synthesis of the T antigen, O-glycan, together with C1GALT1. Cosmc is a multifaceted molecule with a wide range of roles and functions. It involves platelet production and the regulation of immune cell function. Besides that, the loss of function of Cosmc also facilitates the development of several diseases, such as inflammation diseases, immune-mediated diseases, and cancer. It suggests that Cosmc is a critical control point in diseases and that it should be regarded as a potential target for oncotherapy. It is essential to fully comprehend Cosmc's roles, as they may provide critical information about its involvement in disease development and pathogenesis. In this review, we summarize the recent progress in understanding the role of Cosmc in normal development and diseases.

Inflammation-related genes and immune infiltration landscape identified in kainite-induced temporal lobe epilepsy based on integrated bioinformatics analysis.

Temporal lobe epilepsy (TLE) is a common brain disease. However, the pathogenesis of TLE and its relationship with immune infiltration remains unclear. We attempted to identify inflammation-related genes (IRGs) and the immune cell infiltration pattern involved in the pathological process of TLE via bioinformatics analysis. The GSE88992 dataset was downloaded from the Gene Expression Omnibus (GEO) database to perform differentially expressed genes screening and weighted gene co-expression network analysis (WGCNA). Subsequently, the functional enrichment analysis was performed to explore the biological function of the differentially expressed IRGs (DEIRGs). The hub genes were further identified by the CytoHubba algorithm and validated by an external dataset (GSE60772). Furthermore, the CIBERSORT algorithm was applied to assess the differential immune cell infiltration between control and TLE groups. Finally, we used the DGIbd database to screen the candidate drugs for TLE. 34 DEIRGs (33 up-regulated and 1 down-regulated gene) were identified, and they were significantly enriched in inflammation- and immune-related pathways. Subsequently, 4 hub DEIRGs (Ptgs2, Jun, Icam1, Il6) were further identified. Immune cell infiltration analysis revealed that T cells CD4 memory resting, NK cells activated, Monocytes and Dendritic cells activated were involved in the TLE development. Besides, there was a significant correlation between hub DEIRGs and some of the specific immune cells. 4 hub DEIRGs (Ptgs2, Jun, Icam1, Il6) were associated with the pathogenesis of TLE via regulation of immune cell functions, which provided a novel perspective for the understanding of TLE.

Reshaping the tumor microenvironment: The versatility of immunomodulatory drugs in B-cell neoplasms.

Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide and pomalidomide are antitumor compounds that have direct tumoricidal activity and indirect effects mediated by multiple types of immune cells in the tumor microenvironment (TME). IMiDs have shown remarkable therapeutic efficacy in a set of B-cell neoplasms including multiple myeloma, B-cell lymphomas and chronic lymphocytic leukemia. More recently, the advent of immunotherapy has revolutionized the treatment of these B-cell neoplasms. However, the success of immunotherapy is restrained by immunosuppressive signals and dysfunctional immune cells in the TME. Due to the pleiotropic immunobiological properties, IMiDs have shown to generate synergetic effects in preclinical models when combined with monoclonal antibodies, immune checkpoint inhibitors or CAR-T cell therapy, some of which were successfully translated to the clinic and lead to improved responses for both first-line and relapsed/refractory settings. Mechanistically, despite cereblon (CRBN), an E3 ubiquitin ligase, is considered as considered as the major molecular target responsible for the antineoplastic activities of IMiDs, the exact mechanisms of action for IMiDs-based TME re-education remain largely unknown. This review presents an overview of IMiDs in regulation of immune cell function and their utilization in potentiating efficacy of immunotherapies across multiple types of B-cell neoplasms.

Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC.

Most of the primary hepatocellular carcinoma (HCC) develops from Viral Hepatitis including Hepatitis B virus, Hepatitis C Virus, and Nonalcoholic Steatohepatitis. Herein, T cells play crucial roles combined with chronic inflammation and chronic viral infection. However, T cells are gradually exhausted under chronic antigenic stimulation, which leads to T cell exhaustion in the tumor microenvironment, and the exhaustion is associated with mitochondrial dysfunction in T cells. Meanwhile, mitochondria play a crucial role in altering T cells’ metabolism modes to achieve desirable immunological responses, wherein mitochondria maintain quality control (MQC) and promote metabolism regulation in the microenvironment. Although immune checkpoint inhibitors have been widely used in clinical practice, there are some limitations in the therapeutic effect, thus combining immune checkpoint inhibitors with targeting mitochondrial biogenesis may enhance cellular metabolic adaptation and reverse the exhausted state. At present, several studies on mitochondrial quality control in HCC have been reported, however, there are gaps in the regulation of immune cell function by mitochondrial metabolism, particularly the modulating of T cell immune function. Hence, this review summarizes and discusses existing studies on the effects of MQC on T cell populations in liver diseases induced by HCC, it would be clued by mitochondrial quality control events.

Abstract PR001: Oncogene-induced matrix reorganization controls CD8+ T cell immunity in the UPS microenvironment

Abstract CD8+ T cell dysfunction, characterized by reduced effector function, impaired proliferation, and inhibitory receptor upregulation, is a fundamental barrier to anti-tumor immunity. However, molecular mechanisms underlying the regulation of CD8+ T cell dysfunction in the tumor microenvironment (TME) are incompletely understood. In solid cancers, the extracellular matrix (ECM) facilitates tumor progression in part by inhibiting T cell migration/infiltration, but the impact of individual tumor-associated ECM molecules on T cell function remains unclear. Therefore, we investigated the regulation and impact of ECM composition on CD8+ T cell function in muscle-derived undifferentiated pleomorphic sarcoma (UPS). UPS exhibits durable responses to checkpoint therapy in a subset of human patients, potentially offering valuable insights into strategies for ameliorating T cell function and improving patient responses to immunotherapy. Using the autochthonous Kras G12D/+; Trp53 fl/fl (KP) murine model of UPS, we previously showed that deletion of the central Hippo pathway effector Yap1 (Kras G12D/+; Trp53 fl/fl; Yap1 fl/fl; KPY) suppressed UPS cell proliferation and tumor progression. Given the well-established role of Yap1 in mechanotransduction, we leveraged this system to investigate the effects of Yap1 on the ECM and CD8+ T cell function in UPS. We discovered that loss of UPS-cell intrinsic Yap1 reduced the proportion of dysfunctional CD8+ T cells in the TME and enhanced T cell cytolytic capacity. Yap1 loss also downregulated expression of multiple collagen genes in UPS cells and bulk tumors, including those that encode collagen type VI (ColVI). ColVI is a beaded microfilament collagen that binds to fibril-forming collagens in the ECM, such as collagen type I (ColI), and has been implicated in the pathogenesis of skeletal muscle myopathies. These data suggest that proper ColVI structure and function are critical for normal skeletal muscle physiology, with important implications for muscle-derived tumors such as UPS. Accordingly, COL6A1 was upregulated in human UPS relative to normal skeletal muscle, and inversely associated with UPS patient survival. Moreover, loss of UPS cell-intrinsic Col6a1 suppressed tumor progression, enhanced T cell cytolytic function, and attenuated CD8+ T cell exhaustion, phenocopying the effects of Yap1 deletion. Mechanistically, Yap1-mediated ColVI deposition promoted CD8+ T cell dysfunction by remodeling ColI networks in the UPS TME, and inhibiting T cell autophagic flux. Furthermore, ColI depletion dramatically increased tumor growth in an immunocompetent setting. Our findings reveal a novel role for UPS cell-intrinsic Yap1 in immune activation, and demonstrate that ColVI and ColI have opposing functions downstream of Yap in this context. These results underscore the need to systematically evaluate the roles of individual ECM components in the regulation of immune cell function, and implicate YAP1 and/or COLVI targeting as potential strategies for improving the efficacy of immunotherapy in human patients. Citation Format: Ashley M. Fuller, Hawley C. Pruitt, Hoogeun Song, Ying Liu, Ann Devine, Rohan S. Katti, Samir Devalaraja, Gabrielle E. Ciotti, Michael Gonzalez, Erik F. Williams, Ileana Murazzi, Nicolas Skuli, Hakon Hakonarson, Kristy Weber, Malay Haldar, Joseph A. Fraietta, Sharon Gerecht, T. S. Karin Eisinger-Mathason. Oncogene-induced matrix reorganization controls CD8+ T cell immunity in the UPS microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR001.

RIG-I-like Receptor Regulation of Immune Cell Function and Therapeutic Implications.

Retinoic acid-inducible gene I-like receptors (RLRs) are cytosolic RNA sensors critical for initiation of antiviral immunity. Activation of RLRs following RNA recognition leads to production of antiviral genes and IFNs for induction of broad antiviral immunity. Although the RLRs are ubiquitously expressed, much of our understanding of these molecules comes from their study in epithelial cells and fibroblasts. However, RLR activation is critical for induction of immune function and long-term protective immunity. Recent work has focused on the roles of RLRs in immune cells and their contribution to programming of effective immune responses. This new understanding of RLR function in immune cells and immune programming has led to the development of vaccines and therapeutics targeting the RLRs. This review covers recent advances in our understanding of the contribution of RLRs to immune cell function during infection and the emerging RLR-targeting strategies for induction of immunity against cancer and viral infection.

LncRNA pair as candidate diagnostic signature for colorectal cancer based on the within-sample relative expression levels.

BackgroundEarly diagnosis of colorectal cancer could significantly improve the prognosis and reduce mortality. However, indeterminate diagnosis is often met in pathology diagnosis in biopsy samples. Abnormal expression of long non-coding RNA (lncRNA) is associated with the initiation and progression of colorectal cancer. It is of great value and clinical significance to explore lncRNAs as candidate diagnostic biomarkers in colorectal cancer.MethodsBased on the within-sample relative expression levels of lncRNA pairs, we identified a group of candidate diagnostic biomarkers for colorectal cancer. In addition, we validated it in independent datasets produced by different laboratories and different platforms. We also tested it in colorectal cancer tissue samples using quantitative real-time polymerase chain reaction (RT-qPCR).ResultsA biomarker consisting of six lncRNA pairs including nine lncRNAs was identified for the diagnosis of colorectal cancer. For a total of 950 cancer samples and 247 non-cancer samples, both of the sensitivity and specificity could achieve approximately 90%. For adenoma samples, the accuracy could achieve 73%. For normal tissues from inflammatory bowel disease patients, 93% (14/15) were correctly classified as non-cancer. Furthermore, the lncRNA pair biomarker showed excellent performance in all clinical stages; even in the early stage, the accuracy could achieve 87% and 82% in stage I and II. Meanwhile, the biomarker was also robust to the microsatellite instability status. More importantly, we measured the biomarker in 35 colorectal cancer and 30 cancer-adjacent tissue samples using quantitative real-time polymerase chain reaction (RT-qPCR). The accuracy could achieve 93.3% (70/75). Specially, even in early-stage tumors (I and II), the accuracy could also achieve 90.9% (30/33). The enrichment analysis revealed that these lncRNAs were involved in highly associated cancer pathways and immune-related pathways. Immune analysis showed that these marker lncRNAs were associated with multiple immune cells, implying that they might be involved in the regulation of immune cell functions in colorectal cancer. Most of the biomarker lncRNAs were also differentially expressed between the mutant group and wild-type group of colorectal cancer driver genes.ConclusionWe identified and validated six lncRNA pairs including nine lncRNAs as a biomarker for assisting in the diagnosis of colorectal cancer.