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International Journal of Molecular... Jul 2023The search for new and effective treatment targets for cancer immunotherapy is an ongoing challenge. Alongside the more established inhibitory immune checkpoints, a... (Review)
Review
The search for new and effective treatment targets for cancer immunotherapy is an ongoing challenge. Alongside the more established inhibitory immune checkpoints, a novel potential target is CD73. As one of the key enzymes in the purinergic signalling pathway CD73 is responsible for the generation of immune suppressive adenosine. The expression of CD73 is higher in tumours than in the corresponding healthy tissues and associated with a poor prognosis. CD73, mainly by the production of adenosine, is critical in the suppression of an adequate anti-tumour immune response, but also in promoting cancer cell proliferation, tumour growth, angiogenesis, and metastasis. The upregulation of CD73 and generation of adenosine by tumour or tumour-associated immune cells is a common resistance mechanism to many cancer treatments such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Therefore, the inhibition of CD73 represents a new and promising approach to increase therapy efficacy. Several CD73 inhibitors have already been developed and successfully demonstrated anti-cancer activity in preclinical studies. Currently, clinical studies evaluate CD73 inhibitors in different therapy combinations and tumour entities. The initial results suggest that inhibiting CD73 could be an effective option to augment anti-cancer immunotherapeutic strategies. This review provides an overview of the rationale behind the CD73 inhibition in different treatment combinations and the role of CD73 as a prognostic marker.
Topics: Humans; 5'-Nucleotidase; Adenosine; Clinical Relevance; Immunosuppression Therapy; Immunotherapy; Neoplasms
PubMed: 37511518
DOI: 10.3390/ijms241411759 -
Frontiers in Immunology 2023Blood vessels are a key target for cancer therapy. Compared with the healthy vasculature, tumor blood vessels are extremely immature, highly permeable, and deficient in... (Review)
Review
Blood vessels are a key target for cancer therapy. Compared with the healthy vasculature, tumor blood vessels are extremely immature, highly permeable, and deficient in pericytes. The aberrantly vascularized tumor microenvironment is characterized by hypoxia, low pH, high interstitial pressure, and immunosuppression. The efficacy of chemotherapy, radiotherapy, and immunotherapy is affected by abnormal blood vessels. Some anti-angiogenic drugs show vascular normalization effects in addition to targeting angiogenesis. Reversing the abnormal state of blood vessels creates a normal microenvironment, essential for various cancer treatments, specifically immunotherapy. In addition, immune cells and molecules are involved in the regulation of angiogenesis. Therefore, combining vascular normalization with immunotherapy may increase the efficacy of immunotherapy and reduce the risk of adverse reactions. In this review, we discussed the structure, function, and formation of abnormal vessels. In addition, we elaborated on the role of the immunosuppressive microenvironment in the formation of abnormal vessels. Finally, we described the clinical challenges associated with the combination of immunotherapy with vascular normalization, and highlighted future research directions in this therapeutic area.
Topics: Humans; Neoplasms; Immunotherapy; Immunosuppression Therapy; Angiogenesis Inhibitors; Cross Reactions; Tumor Microenvironment
PubMed: 38193080
DOI: 10.3389/fimmu.2023.1291530 -
Pathology, Research and Practice Sep 2023Macrophages are plastic and functionally diverse, present in all tissues, and play a key role in organisms from development, homeostasis and repair, to immune responses... (Review)
Review
Macrophages are plastic and functionally diverse, present in all tissues, and play a key role in organisms from development, homeostasis and repair, to immune responses to pathogens. They are central to many disease states and have emerged as important therapeutic targets for many diseases. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and are key factors influencing cancer progression, metastasis and tumor recurrence. TAMs can be derived from different sources and exert different pro- or anti-tumor effects based on the type, stage and immune composition of the tumor. TAMs are highly heterogeneous and diverse, and have multiple functional phenotypes. There is still a great deal of controversy regarding the relationship between TAMs and prognosis of cancer patients. In this review, we summarize the characteristics of common markers of TAMs as well as explore the prognostic role of TAMs in different cancers including lung, breast, gastric, colorectal, esophageal and ovarian cancers.
Topics: Tumor-Associated Macrophages; Neoplasms; Humans; Biomarkers, Tumor; Prognosis; Immunosuppression Therapy
PubMed: 37544129
DOI: 10.1016/j.prp.2023.154739 -
Frontiers in Immunology 2023
Topics: Humans; Acute-On-Chronic Liver Failure; Immunosuppression Therapy; Immune Tolerance
PubMed: 37662960
DOI: 10.3389/fimmu.2023.1260749 -
Die Anaesthesiologie Nov 2023Organ transplant patients who must undergo nontransplant surgical interventions can be challenging for the anesthesiologists in charge. On the one hand, it is important... (Review)
Review
Organ transplant patients who must undergo nontransplant surgical interventions can be challenging for the anesthesiologists in charge. On the one hand, it is important to carefully monitor the graft function in the perioperative period with respect to the occurrence of a possible rejection reaction. On the other hand, the ongoing immunosuppression may have to be adapted to the perioperative requirements in terms of the active substance and the route of administration, the resulting increased risk of infection and possible side effects (e.g., myelosuppression, nephrotoxicity and impairment of wound healing) must be included in the perioperative treatment concept. Furthermore, possible persistent comorbidities of the underlying disease and physiological peculiarities as a result of the organ transplantation must be taken into account. Support can be obtained from the expertise of the respective transplantation center.
Topics: Humans; Organ Transplantation; Anesthesia; Immunosuppression Therapy
PubMed: 37874343
DOI: 10.1007/s00101-023-01332-x -
Indian Journal of Ophthalmology Sep 2023The management of an episode of corneal graft rejection (CGR) is primarily by corticosteroids. Immunomodulators are useful for long-term immunosuppression and in dealing... (Review)
Review
The management of an episode of corneal graft rejection (CGR) is primarily by corticosteroids. Immunomodulators are useful for long-term immunosuppression and in dealing with cases of high-risk (HR) corneal grafts. The classical signs of CGR following penetrating keratoplasty (PKP) include rejection line, anterior chamber (AC) reaction, and graft edema. However, these signs may be absent or subtle in cases of endothelial keratoplasty (EK). Prevention of an episode of graft rejection is of utmost importance as it can reduce the need for donor cornea significantly. In our previous article (IJO_2866_22), we had discussed about the immunopathogenesis of CGR. In this review article, we aim to discuss the various clinical aspects and management of CGR.
Topics: Humans; Graft Rejection; Corneal Diseases; Corneal Transplantation; Cornea; Immunosuppression Therapy
PubMed: 37602601
DOI: 10.4103/IJO.IJO_228_23 -
British Journal of Anaesthesia Mar 2024Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) is a clinical endotype of chronic critical illness. PICS consists of a self-perpetuating cycle... (Review)
Review
Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) is a clinical endotype of chronic critical illness. PICS consists of a self-perpetuating cycle of ongoing organ dysfunction, inflammation, and catabolism resulting in sarcopenia, immunosuppression leading to recurrent infections, metabolic derangements, and changes in bone marrow function. There is heterogeneity regarding the definition of PICS. Currently, there are no licensed treatments specifically for PICS. However, findings can be extrapolated from studies in other conditions with similar features to repurpose drugs, and in animal models. Drugs that can restore immune homeostasis by stimulating lymphocyte production could have potential efficacy. Another treatment could be modifying myeloid-derived suppressor cell (MDSC) activation after day 14 when they are immunosuppressive. Drugs such as interleukin (IL)-1 and IL-6 receptor antagonists might reduce persistent inflammation, although they need to be given at specific time points to avoid adverse effects. Antioxidants could treat the oxidative stress caused by mitochondrial dysfunction in PICS. Possible anti-catabolic agents include testosterone, oxandrolone, IGF-1 (insulin-like growth factor-1), bortezomib, and MURF1 (muscle RING-finger protein-1) inhibitors. Nutritional support strategies that could slow PICS progression include ketogenic feeding and probiotics. The field would benefit from a consensus definition of PICS using biologically based cut-off values. Future research should focus on expanding knowledge on underlying pathophysiological mechanisms of PICS to identify and validate other potential endotypes of chronic critical illness and subsequent treatable traits. There is unlikely to be a universal treatment for PICS, and a multimodal, timely, and personalised therapeutic strategy will be needed to improve outcomes for this growing cohort of patients.
Topics: Animals; Humans; Critical Illness; Syndrome; Immunosuppression Therapy; Inflammation; Chronic Disease; Research
PubMed: 38177003
DOI: 10.1016/j.bja.2023.11.052 -
Cancer Letters Oct 2023Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in the world. Among many identified risk factors, immunosuppression is a major factor that... (Review)
Review
Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in the world. Among many identified risk factors, immunosuppression is a major factor that contributes to cSCC development. Organ transplant recipients (OTRs) are at markedly increased risk of developing multiple cSCCs with a propensity for advanced metastatic disease, leading to significant morbidity and mortality. The severity of the cSCC phenotype in OTRs highlights the urgent need to identify effective preventive modalities in this population. Despite recent advances in skin cancer prevention (e.g., nicotinamide) and treatment (e.g., immune checkpoint blockade), these modalities have limited utility in OTRs due to the lack of efficacy or significant side effect. Topical treatments against precancerous skin lesions, actinic keratosis (AK), remain the primary strategy to prevent cSCC in OTRs, which also have significant deficiencies in this population. Herein, we review the epidemiology, risk factors, and current cSCC prevention strategies. We highlight the gaps and future clinical strategies to address cSCC risk in high-risk populations.
Topics: Humans; Carcinoma, Squamous Cell; Skin Neoplasms; Immunosuppression Therapy
PubMed: 37734530
DOI: 10.1016/j.canlet.2023.216406 -
The Surgical Clinics of North America Feb 2024Since the first successful liver transplant in 1967, immunosuppression has allowed liver transplantation to become the standard treatment of end-stage liver disease.... (Review)
Review
Since the first successful liver transplant in 1967, immunosuppression has allowed liver transplantation to become the standard treatment of end-stage liver disease. Over the decades, the rates of rejection have decreased, and patient survival outcomes have significantly improved in large part due to the introduction and advancements of immunosuppression medications. However, the adverse effects associated with long-term immunosuppression have created new challenges facing liver transplantation and added significantly to posttransplantation morbidity. This review presents the data and rationale for immunosuppression approaches, addresses the main controversies related to immunosuppression in liver transplantation, and explores some of the newer advancements in immunosuppressive drug therapy.
Topics: Humans; Liver Transplantation; Immunosuppressive Agents; Immunosuppression Therapy; Graft Rejection
PubMed: 37953030
DOI: 10.1016/j.suc.2023.08.004 -
Journal of the National Cancer Institute Nov 2023We investigated the role of A2B-adenosine receptor in regulating immunosuppressive metabolic stress in the tumor microenvironment. Novel A2B-adenosine receptor...
BACKGROUND
We investigated the role of A2B-adenosine receptor in regulating immunosuppressive metabolic stress in the tumor microenvironment. Novel A2B-adenosine receptor antagonist PBF-1129 was tested for antitumor activity in mice and evaluated for safety and immunologic efficacy in a phase I clinical trial of patients with non-small cell lung cancer.
METHODS
The antitumor efficacy of A2B-adenosine receptor antagonists and their impact on the metabolic and immune tumor microenvironment were evaluated in lung, melanoma, colon, breast, and epidermal growth factor receptor-inducible transgenic cancer models. Employing electron paramagnetic resonance, we assessed changes in tumor microenvironment metabolic parameters, including pO2, pH, and inorganic phosphate, during tumor growth and evaluated the immunologic effects of PBF-1129, including its pharmacokinetics, safety, and toxicity, in patients with non-small cell lung cancer.
RESULTS
Levels of metabolic stress correlated with tumor growth, metastasis, and immunosuppression. Tumor interstitial inorganic phosphate emerged as a correlative and cumulative measure of tumor microenvironment stress and immunosuppression. A2B-adenosine receptor inhibition alleviated metabolic stress, downregulated expression of adenosine-generating ectonucleotidases, increased expression of adenosine deaminase, decreased tumor growth and metastasis, increased interferon γ production, and enhanced the efficacy of antitumor therapies following combination regimens in animal models (anti-programmed cell death 1 protein vs anti-programmed cell death 1 protein plus PBF-1129 treatment hazard ratio = 11.74 [95% confidence interval = 3.35 to 41.13], n = 10, P < .001, 2-sided F test). In patients with non-small cell lung cancer, PBF-1129 was well tolerated, with no dose-limiting toxicities; demonstrated pharmacologic efficacy; modulated the adenosine generation system; and improved antitumor immunity.
CONCLUSIONS
Data identify A2B-adenosine receptor as a valuable therapeutic target to modify metabolic and immune tumor microenvironment to reduce immunosuppression, enhance the efficacy of immunotherapies, and support clinical application of PBF-1129 in combination therapies.
Topics: Humans; Animals; Mice; Carcinoma, Non-Small-Cell Lung; Receptor, Adenosine A2B; Tumor Microenvironment; Lung Neoplasms; Immunosuppression Therapy; Adenosine; Phosphates; Cell Line, Tumor
PubMed: 37195421
DOI: 10.1093/jnci/djad091