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Trends in Cancer Oct 2019Checkpoint blockade immunotherapy (CBT) has revolutionized cancer treatment; however, the cellular and molecular factors that govern responsiveness to immunotherapy... (Review)
Review
Checkpoint blockade immunotherapy (CBT) has revolutionized cancer treatment; however, the cellular and molecular factors that govern responsiveness to immunotherapy remain poorly understood. One emerging area of clinical importance is differential responsiveness to CBT across different tissue sites of tumor growth. Each tissue site in the body can contain unique tissue-resident immune cells from both the lymphoid and the myeloid compartment and differences in tissue-specific immune cell composition might predispose tumors in certain tissue sites to be more or less responsive to immunotherapy. Understanding the interplay between tissue-resident and systemic immune responses against tumors will help to determine how to better therapeutically target the immune system to fight cancer. This review summarizes clinical and preclinical investigations of tissue-specific antitumor immune responses and how they influence the tumor immune microenvironment and the efficacy of immunotherapy.
Topics: Animals; Biomarkers, Tumor; Dendritic Cells; Energy Metabolism; Humans; Immunity; Immunity, Innate; Immunotherapy; Molecular Targeted Therapy; Myeloid Cells; Neoplasm Staging; Neoplasms; Organ Specificity; T-Lymphocytes; Tumor Microenvironment
PubMed: 31706507
DOI: 10.1016/j.trecan.2019.07.006 -
Molecular Neurodegeneration Jan 2022Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson's disease (PD). Aggregated α-synuclein pathologically defines PD. Recent...
BACKGROUND
Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson's disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocytes in idiopathic PD, as well as increased phosphorylation of the LRRK2 kinase substrate Rab10 in monocytes in some LRRK2 mutation carriers. Brain-engrafting pro-inflammatory monocytes have been implicated in dopaminergic neurodegeneration in PD models. Here we examine how α-synuclein and LRRK2 interact in monocytes and subsequent neuroinflammatory responses.
METHODS
Human and mouse monocytes were differentiated to distinct transcriptional states resembling macrophages, dendritic cells, or microglia, and exposed to well-characterized human or mouse α-synuclein fibrils. LRRK2 expression and LRRK2-dependent Rab10 phosphorylation were measured with monoclonal antibodies, and myeloid cell responses to α-synuclein fibrils in R1441C-Lrrk2 knock-in mice or G2019S-Lrrk2 BAC mice were evaluated by flow cytometry. Chemotaxis assays were performed with monocyte-derived macrophages stimulated with α-synuclein fibrils and microglia in Boyden chambers.
RESULTS
α-synuclein fibrils robustly stimulate LRRK2 and Rab10 phosphorylation in human and mouse macrophages and dendritic-like cells. In these cells, α-synuclein fibrils stimulate LRRK2 through JAK-STAT activation and intrinsic LRRK2 kinase activity in a feed-forward pathway that upregulates phosphorylated Rab10. In contrast, LRRK2 expression and Rab10 phosphorylation are both suppressed in microglia-like cells that are otherwise highly responsive to α-synuclein fibrils. Corroborating these results, LRRK2 expression in the brain parenchyma occurs in pro-inflammatory monocytes infiltrating from the periphery, distinct from brain-resident microglia. Mice expressing pathogenic LRRK2 mutations G2019S or R1441C have increased numbers of infiltrating pro-inflammatory monocytes in acute response to α-synuclein fibrils. In primary cultured macrophages, LRRK2 kinase inhibition dampens α-synuclein fibril and microglia-stimulated chemotaxis.
CONCLUSIONS
Pathologic α-synuclein activates LRRK2 expression and kinase activity in monocytes and induces their recruitment to the brain. These results predict that LRRK2 kinase inhibition may attenuate damaging pro-inflammatory monocyte responses in the brain.
Topics: Animals; Brain; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice; Monocytes; Mutation; Parkinson Disease; alpha-Synuclein
PubMed: 35012605
DOI: 10.1186/s13024-021-00509-5 -
Theranostics 2021Smart theranostics are dynamic platforms that integrate multiple functions, including at least imaging, therapy, and responsiveness, in a single agent. This review... (Review)
Review
Smart theranostics are dynamic platforms that integrate multiple functions, including at least imaging, therapy, and responsiveness, in a single agent. This review showcases a variety of responsive theranostic agents developed specifically for magnetic resonance imaging (MRI), due to the privileged position this non-invasive, non-ionising imaging modality continues to hold within the clinical imaging field. Different MRI smart theranostic designs have been devised in the search for more efficient cancer therapy, and improved diagnostic efficiency, through the increase of the local concentration of therapeutic effectors and MRI signal intensity in pathological tissues. This review explores novel small-molecule and nanosized MRI theranostic agents for cancer that exhibit responsiveness to endogenous (change in pH, redox environment, or enzymes) or exogenous (temperature, ultrasound, or light) stimuli. The challenges and obstacles in the design and application of responsive theranostics are also discussed to guide future research in this interdisciplinary field towards more controllable, efficient, and diagnostically relevant smart theranostics agents.
Topics: Contrast Media; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Nanoparticles; Neoplasms; Precision Medicine; Theranostic Nanomedicine
PubMed: 34522208
DOI: 10.7150/thno.57004 -
Fa Yi Xue Za Zhi Jun 2020Metabolomics is an interdisciplinary subject that rose in the post-genomic era, which focuses on quantitative study of the response of living organisms to outside... (Review)
Review
Metabolomics is an interdisciplinary subject that rose in the post-genomic era, which focuses on quantitative study of the response of living organisms to outside stimulation and pathophysiological changes, as well as multiple dynamic response of the level of in vivo metabolites caused by genetic mutation. It is extensively used in basic research of system biology, materia medica, clinical medicine, etc. In the forensic field, metabolomics mainly focuses on forensic toxicology, but with the generalization of certain techniques, it's foreseeable that metabolomics has a broad research prospect in forensic pathology. This article summarizes the major analysis techniques and methods of metabolomics, describes the research status of metabolomic techniques in the field of forensic pathology application research, including postmortem interval and death cause. Moreover, this article summarizes and discusses the potential applicable areas, in order to provide reference for relative research and application.
Topics: Autopsy; Forensic Pathology; Forensic Toxicology; Humans; Metabolomics; Postmortem Changes
PubMed: 32705848
DOI: 10.12116/j.issn.1004-5619.2020.03.010 -
Epilepsia Sep 2021The study aimed to identify distinct phenotypes within nonconvulsive status epilepticus (NCSE). Consecutive episodes of NCSE in patients at least 14 years old were...
The study aimed to identify distinct phenotypes within nonconvulsive status epilepticus (NCSE). Consecutive episodes of NCSE in patients at least 14 years old were included. The level of consciousness was assessed through the Glasgow Coma Scale (GCS). Etiology of NCSE was defined as symptomatic (acute, remote, progressive) or unknown. Electroencephalographic (EEG) recordings were searched for lateralized periodic discharges (LPDs), generalized sharply and/or triphasic periodic potentials (GPDs), and spontaneous burst suppression (BS). According to treatment response, NCSE was classified as responsive, refractory, or superrefractory. Average linkage hierarchical cluster analysis was performed with Pearson correlation as similarity measure. Two hundred twenty-nine episodes of NCSE were included. Three clusters were identified. The first cluster linked GCS score 3-8, presence of spontaneous BS on EEG, acute symptomatic etiology, and treatment superrefractoriness. The second cluster gathered GCS score 9-12, presence of LPDs or GPDs on EEG, unknown etiology, and treatment refractoriness. The third cluster associated GCS score 13-15, absence of LPDs, GPDs, and spontaneous BS on EEG, and progressive and remote symptomatic etiology with treatment responsiveness. Phenotyping the heterogeneity of NCSE into electroclinical clusters can contribute to understanding correlations between pathologic and clinical domains, assessing the intrinsic severity of NCSE episodes, and estimating the likelihood of treatment responsiveness.
Topics: Adolescent; Coma; Electroencephalography; Glasgow Coma Scale; Humans; Phenotype; Status Epilepticus
PubMed: 34244997
DOI: 10.1111/epi.16999 -
International Journal of Molecular... Sep 2022Galectins (Gal) are characterized by their affinity for galactoside structures on glycoconjugates. This relationship is mediated by carbohydrate recognition domains,... (Review)
Review
Galectins (Gal) are characterized by their affinity for galactoside structures on glycoconjugates. This relationship is mediated by carbohydrate recognition domains, which are multifunctional regulators of basic cellular biological processes with high structural similarity among family members. They participate in both innate and adaptive immune responses, as well as in reproductive immunology. Recently, the discovery that galectins are highly expressed at the maternal-fetal interface has garnerd the interest of experts in human reproduction. Galectins are involved in a variety of functions such as maternal-fetal immune tolerance, angiogenesis, trophoblast invasion and placental development and are considered to be important mediators of successful embryo implantation and during pregnancy. Dysregulation of these galectins is associated with abnormal and pathological pregnancies (e.g., preeclampsia, gestational diabetes mellitus, fetal growth restriction, preterm birth). Our work reviews the regulatory mechanisms of galectins in normal and pathological pregnancies and has implications for clinicians in the prevention, diagnosis and treatment of pregnancy-related diseases.
Topics: Female; Galectins; Humans; Infant, Newborn; Placenta; Placentation; Pregnancy; Premature Birth; Trophoblasts
PubMed: 36077508
DOI: 10.3390/ijms231710110 -
Experimental Hematology & Oncology Apr 2023We aim to examine the prognostic value of major pathologic response in metastatic lymph nodes (mLN-MPR) after immunochemotherapy in non-small cell lung cancer (NSCLC),...
We aim to examine the prognostic value of major pathologic response in metastatic lymph nodes (mLN-MPR) after immunochemotherapy in non-small cell lung cancer (NSCLC), and demonstrate the pathological characteristic of regression in mLN. Adult patients consecutively undergone neoadjuvant immunochemotherapy and radical-intent surgery for initial stage cIII NSCLC between 2020 and 2021 were included. Hematoxylin- and eosin-stained slides of paraffinembedded sections of the degree of pathologic response in the primary tumor (PT) and its paired involved LNs were reviewed. Imaging mass cytometry was conducted to quantify the immunological status. With 10% as residual viable tumor (RVT) cutoff, mLN-MPR (HR: 0.34, 95%CI: 0.14-0.78; P = 0.011, ref: mLN-MPR(-)) showed more significant correlation with DFS than ypN0 (HR: 0.40, 95%CI: 0.17-0.94; P = 0.036, ref: ypN1-N2). And mLN-MPR combined with PT-MPR, compared with ypN stage combined with PT-MPR (p-value: 0.030 vs. 0.117), can better distinguished the DFS curves of the 4 subgroups of patients. mLN-MPR(+)/PT-MPR(+) patients had the best prognosis compared with other subgroups. Pathologic responses of RVT in PT and paired regional LNs [MPR inconsistency rate: 21/53 (39.6%)], and across different LNs could be inconsistent, especially in squamous cell carcinoma. RVT% in mLNs after immunochemotherapy appeared to be polarized [16 (30.2%) cases with RVT ≥ 70%; 34 (64.2%) with RVT ≤ 10%]. Partial regression of LN metastasis could present with distinct immune subtypes: immune-inflamed or immune-evacuation subtype, and the former presented with higher CD3, CD8, and PD-1 expression in the invasive margin. mLN-MPR demonstrated a potential prognostic value in predicting DFS in patients treated with neoadjuvant immunochemotherapy, but further research is needed to validate its usefulness for other survival outcomes, including OS.
PubMed: 37072866
DOI: 10.1186/s40164-023-00401-6 -
The Oncologist Jun 2023Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well...
BACKGROUND
Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO).
MATERIALS AND METHODS
This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs.
RESULTS
Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9).
CONCLUSIONS
IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era.
PubMed: 37368355
DOI: 10.1093/oncolo/oyad166 -
Molecular Therapy : the Journal of the... Oct 2020Epigenetic alterations occur in many physiological and pathological processes. N-methyladenosine (mA) modification is the most prevalent modification in eukaryotic...
Epigenetic alterations occur in many physiological and pathological processes. N-methyladenosine (mA) modification is the most prevalent modification in eukaryotic mRNAs. However, the role of mA modification in pathological angiogenesis remains elusive. In this study, we showed that the level of mA modification was significantly upregulated in endothelial cells and mouse retinas following hypoxic stress, which was caused by increased METTL3 levels. METTL3 silencing or METTL3 overexpression altered endothelial cell viability, proliferation, migration, and tube formation in vitro. METTL3 knockout in vivo decreased avascular area and pathological neovascular tufts in an oxygen-induced retinopathy model and inhibited alkali burn-induced corneal neovascularization. Mechanistically, METTL3 exerted its angiogenic role by regulating Wnt signaling through the mA modification of target genes (e.g., LRP6 and dishevelled 1 [DVL1]). METTL3 enhanced the translation of LRP6 and DVL1 in an YTH mA RNA-binding protein 1 (YTHDF1)-dependent manner. Collectively, this study suggests that METTL3-mediated mA modification is an important hypoxic stress-response mechanism. The targeting of mA through its writer enzyme METTL3 is a promising strategy for the treatment of angiogenic diseases.
Topics: Adenosine; Animals; Biomarkers; Disease Susceptibility; Epigenesis, Genetic; Gene Expression Regulation; Gene Silencing; Humans; Hypoxia; Methyltransferases; Mice; Mice, Knockout; Neovascularization, Pathologic; RNA, Messenger; Retinal Diseases; Wnt Signaling Pathway
PubMed: 32755566
DOI: 10.1016/j.ymthe.2020.07.022 -
Annals of Oncology : Official Journal... Feb 2024The outcome of patients with resectable mucosal melanoma is poor. Toripalimab combined with axitinib has shown impressive results in metastatic mucosal melanoma with an...
BACKGROUND
The outcome of patients with resectable mucosal melanoma is poor. Toripalimab combined with axitinib has shown impressive results in metastatic mucosal melanoma with an objective response rate of 48.3% and a median progression-free survival of 7.5 months in a phase Ib trial. It was hypothesized that this combination administered in the neoadjuvant setting might induce a pathologic response in resectable mucosal melanoma, so we conducted this trial.
PATIENTS AND METHODS
This single-arm phase II trial enrolled patients with resectable mucosal melanoma. Patients received toripalimab 3 mg/kg once every 2 weeks (Q2W) plus axitinib 5 mg two times a day (b.i.d.) for 8 weeks as neoadjuvant therapy, then surgery and adjuvant toripalimab 3 mg/kg Q2W starting 2 ± 1weeks after surgery for 44 weeks. The primary endpoint was the pathologic response rate according to the International Neoadjuvant Melanoma Consortium recommendations.
RESULTS
Between August 2019 and October 2021, 29 patients were enrolled and received treatment, of whom 24 underwent resection. The median follow-up time was 34.2 months (95% confidence interval 20.4-48.0 months). The pathologic response rate was 33.3% (8/24; 4 pathological complete responses and 4 pathological partial responses). The median event-free survival for all patients was 11.1 months (95% confidence interval 5.3-16.9 months). The median overall survival was not reached. Neoadjuvant therapy was tolerable with 8 (27.5%) grade 3-4 treatment-related adverse events and no treatment-related deaths. Tissue samples of 17 patients at baseline and after surgery were collected (5 responders and 12 nonresponders). Multiplex immunohistochemistry demonstrated a significant increase in CD3+ (P = 0.0032) and CD3+CD8+ (P = 0.0038) tumor-infiltrating lymphocytes after neoadjuvant therapy, particularly in pathological responders.
CONCLUSIONS
Neoadjuvant toripalimab combined with axitinib in resectable mucosal melanoma demonstrated a promising pathologic response rate with significantly increased infiltrating CD3+ and CD3+CD8+ T cells after therapy.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Melanoma; Neoadjuvant Therapy; Neoplasm Staging
PubMed: 37956739
DOI: 10.1016/j.annonc.2023.10.793