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1.
Amino Acid Metabolism in Cancer Drug Resistance.
Yoo, HC, Han, JM
Cells. 2022;(1)
Abstract
Despite the numerous investigations on resistance mechanisms, drug resistance in cancer therapies still limits favorable outcomes in cancer patients. The complexities of the inherent characteristics of tumors, such as tumor heterogeneity and the complicated interaction within the tumor microenvironment, still hinder efforts to overcome drug resistance in cancer cells, requiring innovative approaches. In this review, we describe recent studies offering evidence for the essential roles of amino acid metabolism in driving drug resistance in cancer cells. Amino acids support cancer cells in counteracting therapies by maintaining redox homeostasis, sustaining biosynthetic processes, regulating epigenetic modification, and providing metabolic intermediates for energy generation. In addition, amino acid metabolism impacts anticancer immune responses, creating an immunosuppressive or immunoeffective microenvironment. A comprehensive understanding of amino acid metabolism as it relates to therapeutic resistance mechanisms will improve anticancer therapeutic strategies.
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2.
Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy.
Augustin, RC, Leone, RD, Naing, A, Fong, L, Bao, R, Luke, JJ
Journal for immunotherapy of cancer. 2022;(2)
Abstract
Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and CD39 in development. Through a cyclic-AMP-mediated intracellular cascade, adenosine shifts the cytokine and cellular profile of the tumor microenvironment away from cytotoxic T cell inflammation toward one of immune tolerance. A perpetuating cycle of tumor cell proliferation, tissue injury, dysregulated angiogenesis, and hypoxia promote adenosine accumulation via ATP catabolism. Adenosine receptor (eg, A2AR, A2BR) stimulation of both the innate and adaptive cellular precursors lead to immunosuppressive phenotypic differentiation. Preclinical work in various tumor models with adenosine receptor inhibition has demonstrated restoration of immune cell function and tumor regression. Given the broad activity but known limitations of anti-programmed cell death protein (PD1) therapy and other checkpoint inhibitors, ongoing studies have sought to augment the successful outcomes of anti-PD1 therapy with combinatorial approaches, particularly adenosine signaling blockade. Preliminary data have demonstrated an optimal safety profile and enhanced overall response rates in several early phase clinical trials with A2AR and more recently CD73 inhibitors. However, beneficial outcomes for both monotherapy and combinations have been mostly lower than expected based on preclinical studies, indicating a need for more nuanced patient selection or biomarker integration that might predict and optimize patient outcomes. In the context of known immuno-oncology biomarkers such as tumor mutational burden and interferon-associated gene expression, a comparison of adenosine-related gene signatures associated with clinical response indicates an underlying biology related to immunosuppression, angiogenesis, and T cell inflammation. Importantly, though, adenosine associated gene expression may point to a unique intratumoral phenotype independent from IFN-γ related pathways. Here, we discuss the cellular and molecular mechanisms of adenosine-mediated immunosuppression, preclinical investigation of adenosine signaling blockade, recent response data from clinical trials with A2AR, CD73, CD39 and PD1/L1 inhibitors, and ongoing development of predictive gene signatures to enhance combinatorial immune-based therapies.
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3.
Epigenetic scores for the circulating proteome as tools for disease prediction.
Gadd, DA, Hillary, RF, McCartney, DL, Zaghlool, SB, Stevenson, AJ, Cheng, Y, Fawns-Ritchie, C, Nangle, C, Campbell, A, Flaig, R, et al
eLife. 2022
Abstract
Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.
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4.
Immune Checkpoint Therapies and Atherosclerosis: Mechanisms and Clinical Implications: JACC State-of-the-Art Review.
Vuong, JT, Stein-Merlob, AF, Nayeri, A, Sallam, T, Neilan, TG, Yang, EH
Journal of the American College of Cardiology. 2022;(6):577-593
Abstract
Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced malignancies in recent years. Numerous reports have detailed the myriad of possible adverse inflammatory effects of immune checkpoint therapies, including within the cardiovascular system. However, these reports have been largely limited to myocarditis. The critical role of inflammation and adaptive immunity in atherosclerosis has been well characterized in preclinical studies, and several emerging clinical studies indicate a potential role of immune checkpoint targeting therapies in the development and exacerbation of atherosclerosis. In this review, we provide an overview of the role of T-cell immunity in atherogenesis and describe the molecular effects and clinical associations of both approved and investigational immune checkpoint therapy on atherosclerosis. We also highlight the role of cholesterol metabolism in oncogenesis and discuss the implications of these associations on future treatment and monitoring of atherosclerotic cardiovascular disease in the oncologic population receiving immune checkpoint therapy.
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5.
Metabolic Implications of Immune Checkpoint Proteins in Cancer.
Stirling, ER, Bronson, SM, Mackert, JD, Cook, KL, Triozzi, PL, Soto-Pantoja, DR
Cells. 2022;(1)
Abstract
Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.
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6.
Optimum health and inhibition of cancer progression by microbiome and resveratrol.
Stokes Iii, J, Vinayak, S, Williams, J, Malik, S, Singh, R, Manne, U, Owonikoko, TK, Mishra, MK
Frontiers in bioscience (Landmark edition). 2021;(3):496-517
Abstract
Resveratrol (RES) is a naturally occurring polyphenol found in fruits, green leafy vegetables, and peanuts. This versatile compound, which has potent regenerative, anti-oxidative, and cancer-fighting properties, is produced in plants, particularly in response to stress stimuli. By various mechanisms, including regulation of genes and proteins, RES inhibits the growth of pathogenic bacteria and the development of cancers. The gut has a prominent role in nutrient assimilation, metabolism, immunity, and cancer regression, and the endogenous microbiome protects the host from invasive bacteria that facilitate the progression of various diseases. Short-chain fatty acids (SFCAs) are the byproducts of microbial fermentation in the gastrointestinal tract. Native microflora regulates internal homeostasis, influence the activity of host immune cells, and regress some cancers via the action of SCFAs produced from a plant-based diet. This review shows the relevance of dietary constituents and gut microbial activity in ensuring optimal health of the host.
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7.
CX-072 (pacmilimab), a Probody ® PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study.
Naing, A, Thistlethwaite, F, De Vries, EGE, Eskens, FALM, Uboha, N, Ott, PA, LoRusso, P, Garcia-Corbacho, J, Boni, V, Bendell, J, et al
Journal for immunotherapy of cancer. 2021;(7)
Abstract
BACKGROUND Probody® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing 'off-tumor' toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1). METHODS In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1). RESULTS An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1). CONCLUSIONS Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression. TRIAL REGISTRATION NUMBER NCT03013491.
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8.
Manganese oxide nanomaterials boost cancer immunotherapy.
Ding, B, Yue, J, Zheng, P, Ma, P, Lin, J
Journal of materials chemistry. B. 2021;(35):7117-7131
Abstract
Immunotherapy, a strategy that leverages the host immune function to fight against cancer, plays an increasingly important role in clinical tumor therapy. In spite of the great success achieved in not only clinical treatment but also basic research, cancer immunotherapy still faces many huge challenges. Manganese oxide nanomaterials (MONs), as ideal tumor microenvironment (TME)-responsive biomaterials, are able to dramatically elicit anti-tumor immune responses in multiple ways, indicating great prospects for immunotherapy. In this review, on the basis of different mechanisms to boost immunotherapy, major highlighted topics are presented, covering adjusting an immunosuppressive TME by generating O2 (like O2-sensitized photodynamic therapy (PDT), programmed cell death ligand-1 (PD-L1) expression downregulation, reprogramming tumor-associated macrophages (TAMs), and restraining tumor angiogenesis and lactic acid exhaustion), inducing immunogenic cell death (ICD), photothermal therapy (PTT) induction, activating the stimulator of interferon gene (STING) pathway and immunoadjuvants for nanovaccines. We hope that this review will provide holistic understanding about MONs and their application in cancer immunotherapy, and thus pave the way to the translation from bench to bedside in the future.
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9.
Pro- and Anti- Effects of Immunoglobulin A- Producing B Cell in Tumors and Its Triggers.
Zhong, Z, Nan, K, Weng, M, Yue, Y, Zhou, W, Wang, Z, Chu, Y, Liu, R, Miao, C
Frontiers in immunology. 2021;:765044
Abstract
B cells are well known as key mediators of humoral immune responses via the production of antibodies. Immunoglobulin A (IgA) is the most abundantly produced antibody isotype and provides the first line of immune protection at mucosal surfaces. However, IgA has long been a divisive molecule with respect to tumor progression. IgA exerts anti- or pro-tumor effect in different tumor types. In this review, we summarize emerging evidence regarding the production and effects of IgA and IgA+ cells in the tumor microenvironment (TME). Moreover, we discuss that the TME cytokines, host diet, microbiome, and metabolites play a pivotal role in controlling the class-switch recombination (CSR) of IgA. The analysis of intratumoral Ig repertoires and determination of metabolites that influence CSR may help establish novel therapeutic targets for the treatment of cancers.
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10.
Lactoferrin may inhibit the development of cancer via its immunostimulatory and immunomodulatory activities (Review).
Pan, S, Weng, H, Hu, G, Wang, S, Zhao, T, Yao, X, Liao, L, Zhu, X, Ge, Y
International journal of oncology. 2021;(5)
Abstract
Lactoferrin (Lf) is secreted by ectodermal tissue and has a structure similar to that of transferrin. Although Lf seems to be multifunctional, its main function is related to the natural defense system of mammals. The present review aims to highlight the major actions of Lf, including the regulation of cell growth, the inhibition of toxic compound formation, the removal of harmful free radicals and its important role in immune response regulation. Moreover, Lf has antibacterial, antiviral, antioxidant, anticancer and anti‑inflammatory activities. In addition, the use of Lf for functionalization of drug nanocarriers, with emphasis on tumor‑targeted drug delivery, is illustrated. Such effects serve as an important theoretical basis for its future development and application. In neurodegenerative diseases and the brains of elderly people, Lf expression is markedly upregulated. Lf may exert an anti‑inflammatory effect by inhibiting the formation of hydroxyl free radicals. Through its antioxidant properties, Lf can prevent DNA damage, thereby preventing tumor formation in the central nervous system. In addition, Lf specifically activates the p53 tumor suppressor gene.