Cell Immune Surveillance Research Articles

Actin Retrograde Flow Regulated by the Wiskott-Aldrich Syndrome Protein Drives the Natural Killer Cell Response.

Simple SummaryImmune cells sense mechanical stimuli from their microenvironment by transducing them into biochemical signals through mechanosensors, in a process called mechanotransduction. The cytoskeleton mediates mechanotransduction in response to local environmental changes. The cytoskeletal component, actin, provides the structural basis for the NK cell immunological synapse (NKIS) and polarization of the signaling complex and secretory apparatus. Actin-mediated mechanotransduction is essential to adjust and to improve the natural killer (NK) cell response to changes induced by the microenvironment. Wiskott–Aldrich Syndrome protein (WASp), another key cytoskeletal component, plays a role in actin filament nucleation, and hence it’s branching toward the membrane. Here, we found that WASp regulates mechanotransduction by controlling F-actin movement thereby modulating NK cell signaling and the equilibrium between activation versus inhibition. WASp regulation of the actin retrograde flow (ARF) provides a novel mechanism to modulate the functional outcome of NK cells in response to their environment.Understanding the crosstalk between natural killer (NK) cells and the tumor microenvironment (TME) has enhanced the potential of exploiting the interplay between activation and inhibition of NK cells for immunotherapy. This interaction is crucial for understanding how tumor cells escape NK cell immune surveillance. NK cell dysfunction is regulated by two molecular mechanisms, downregulated activating receptor ligand expression on the tumor cells, and upregulated inhibitory signals delivered to NK cells. Recent studies demonstrated the role of mechanotransduction in modulating NK cell responses in the TME. The immunological synapse represents a functional interface between the NK cell and its target, regulated by Actin Retrograde Flow (ARF), which drives the adhesion molecules and receptors toward the central zone of the immunological synapse (IS). Here, we further characterize the role of ARF in controlling the immune response of NK cells, using CRISPR/cas9-mediated Wiskott–Aldrich Syndrome protein (WASp) gene silencing of NK cells. We demonstrate that WASp regulates ARF velocity, affecting the conformation and function of the key NK inhibitory regulator, SH2-domain containing protein tyrosine phosphatase-1 (SHP-1), and consequently, the NK cell response. Our results demonstrate the potential of modulating the biophysical and intracellular regulation of NK activation as a promising approach for improving immunotherapy.

Understanding the mechanisms of gallbladder lesions: A systematic review.

The gallbladder undergoes different types of pathologies, ranging from inflammatory to preneoplasia and finally to malignant lesions. Gallbladder carcinoma can be highly invasive, and it is known that chronic inflammation of the gallbladder can lead to preneoplastic abnormalities and subsequently malignant phenotypes. Gallbladder neoplasia has a low incidence but is associated with a very poor prognosis. An early diagnosis is therefore extremely important in order to improve the prognosis of patients. Immunohistochemical markers of the mucin family can distinguish between different types of gallbladder lesions. Mucins are glycoproteins that can be attached to threonine residues that are O-glycosylated (due to the hydroxyl group of this amino acid). Mucins are divided into two types: those that bind to the membrane, such as MUC1, and those that form gels or are secreted, such as MUC5AC. Various alterations in mucin expression have been revealed to be associated with the development of neoplasia, as they modulate cell growth, karyokinetic transformation, dedifferentiation, adhesion, invasion and immune surveillance. p53 is a tumor suppressor gene and is linked to the development of different types of neoplasia. The incidence of the p53 gene is variable in the pathophysiology of gallbladder cancer. Several studies have revealed an incidence of ~50% of the p53 gene in gallbladder tumors. Studying the immunohistochemical profile of mucins and the presence of different gene mutations in neoplastic lesions of the gallbladder and surrounding mucosa may contribute to the understanding of the pathophysiology of the disease and the mechanisms involved in tumor development, allowing the identification of patients at increased risk of developing neoplasia, thus leading to improved management.

Abstract 3506: CLN-619, a clinical-stage MICA/MICB-specific IgG1 antibody, restores the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis

Abstract Natural killer (NK) cells play a central role in the immune surveillance of cancer. NK cells express multiple inhibitory and activating surface receptors, including the activating receptor, NKG2D. Engagement of NKG2D by the stress-induced ligands MICA/MICB stimulates NK cell activation and subsequent target cell lysis. While MICA/MICB expression is restricted in normal tissues, expression is strongly induced upon viral infection, genotoxic stress or malignant transformation. In cancer patients, the tumor microenvironment (TME) facilitates evasion of immune surveillance by NK cells. One mechanism by which tumor cells can escape NKG2D-mediated lysis is via proteolytic release of MICA/MICB from the cell surface due to proteases present in the TME. High concentrations of shed MICA have been observed in serum from patients across multiple tumor types and correlate with poor survival. In mouse models, expression of MICA on tumor cells delayed tumor growth, while the absence of NKG2D accelerated tumor growth. Given the established role of the MICA/MICB-NKG2D axis in the immune surveillance of tumor cells, a therapeutic agent that effectively restores this axis is a compelling approach to harness the immune system for treating cancer. CLN-619 is a humanized anti-MICA/MICB monoclonal IgG1 antibody being developed for the treatment of multiple cancer indications. The antibody was selected based on its high-affinity binding to MICA/MICB, potent in vitro activity and robust anti-tumor activity in xenograft models. MICA/MICB is highly polymorphic, with >150 MICA and 47 MICB alleles in humans, and expression level, binding affinity to NKG2D, and degree of MICA/MICB shedding is thought to be allele-dependent. CLN-619 demonstrated high affinity binding to all common allelic variants of MICA, including the most prevalent MICA allele, MICA*008, and the canonical allelic variant of MICB. CLN-619 was able to prevent proteolytic cleavage of MICA/MICB as evidenced by the reduction of shed MICA/MICB in cell culture supernatants and the corresponding increase in surface MICA/MICB on cancer cells. In addition to the ability to restore the MICA/MICB-NKG2D axis, CLN-619 enhanced the binding of MICA to NKG2D on NK cells. This was enabled by both FcγR engagement on NK cells as well as an intrinsic enhancement of MICA binding to NKG2D. Finally, CLN-619 was shown to elicit potent ADCC of MICA/MICB expressing tumor cells. Consistent with the multimodal mechanisms of action described above, CLN-619 treatment resulted in robust anti-tumor activity at low doses in mice bearing MICA/MICB-expressing human tumor xenografts. Given the pan-cancer expression of MICA/MICB in both solid and hematological malignancies, CLN-619 is expected to have broad anti-tumor activity. CLN-619 is currently being investigated in a Phase 1 clinical trial for the treatment of patients with advanced solid tumors. Citation Format: Kerry A. Whalen, Naveen K. Mehta, Safak Yalcin, Kristan Meetze, Neil W. Gibson, Jennifer S. Michaelson, Patrick A. Baeuerle. CLN-619, a clinical-stage MICA/MICB-specific IgG1 antibody, restores the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3506.

Advances in Immune Microenvironment and Immunotherapy of Isocitrate Dehydrogenase Mutated Glioma.

The tumor immune microenvironment and immunotherapy have become current important tumor research concerns. The unique immune microenvironment plays a crucial role in the malignant progression of isocitrate dehydrogenase (IDH) mutant gliomas. IDH mutations in glioma can inhibit tumor-associated immune system evasion of NK cell immune surveillance. Meanwhile, mutant IDH can inhibit classical and alternative complement pathways and directly inhibit T-cell responses by metabolizing isocitrate to D-2-Hydroxyglutaric acid (2-HG). IDH has shown clinically relevant efficacy as a potential target for immunotherapy. This article intends to summarize the research progress in the immunosuppressive microenvironment and immunotherapy of IDH-mutant glioma in recent years in an attempt to provide new ideas for the study of occurrence, progression, and treatment of IDH-mutant glioma.

Tumor-Derived Exosomes Regulate Apoptosis of CD45+EpCAM+ Cells in Lung Cancer.

Lung cancer has the highest mortality rate among human cancers, and the majority of deaths result from metastatic spread. The tumor microenvironment plays an important role in suppressing the immune surveillance and elimination of tumor cells. A few studies have reported the presence of CD45+EpCAM+ double-positive cells in cancer, but the underlying mechanism remains unclear with respect to how these cells originate and their function in cancer biology. In this study, we analyzed 25 lung tumor samples. We confirmed the presence of CD45+EpCAM+ cells in lung cancer, and these cells exhibited higher apoptosis than CD45+EpCAM− cells. Using co-culture of lung cancer cell-derived exosomes with healthy donor peripheral blood mononuclear cells, we recapitulated CD45+EpCAM+ cell formation and increased apoptosis that occurs in patients with primary lung cancer. Further analysis suggested that microRNAs in lung cancer cell-derived exosomes may alter the gene expression profile of CD45+EpCAM+ cells, resulting in elevated TP53 expression and increased apoptosis. To our knowledge, this is the first report of cancer cell-derived exosomes that can inhibit the immune system by promoting immune cell apoptosis.

Investigating Susceptibility of ꞵ‐catenin‐mutated Hepatocellular Carcinoma to Checkpoint Inhibitors

Hepatocellular Carcinoma (HCC) is the 5th most common cause of cancer‐related death in the United States with an estimated 32,000 annual deaths. The standard of care for HCC as established by the IMBrave150 trial is a combination of the PD‐L1 inhibitor, Atezolizumab, and an antiangiogenic, Bevacizumab. While this combination extends overall survival to 19.2 months in unresectable HCC, only 52% of patients survive to 18 months. Furthermore, objective response rates are around 32% and hence clarifying underlying mechanisms regulating the immune response in HCC oncogenesis might strengthen immunotherapy efficacy. Especially important is to identify response rates of these agents in specific molecular subclasses of HCC may help in better patient selection. The oncogene ꞵ‐catenin is consistently mutated and activated among 30% of HCC patients. The Wnt/ꞵ‐catenin pathway has been approached as a target for precision medicine in HCC. We recently modeled HCCs with ꞵ‐catenin mutations in mice up to 69% genetic similarity. Here, we combine hydrodynamic tail vein injections with the Sleeping Beauty Transposase which is a non‐viral method of expressing genes of interest. Our model co‐expresses an S45Y point mutant of ꞵ‐catenin with the tyrosine kinase receptor MET (B+M). This combination represents ~10% of patient HCCs and provides a clinically relevant tool for the investigation of personalized HCC therapeutics.A recent study demonstrated HCCs driven by a Δ90‐truncation mutant of ꞵ‐catenin in combination with the Myc oncogene are shown to lack sufficient immune cell surveillance. These HCCs have poor cytotoxic T cell and dendritic cell recruitment while responding poorly to checkpoint inhibitors. Since activating point mutations in CTNNB1 gene are common in patient HCCs, we asked whether poor immune surveillance extends to HCC models harboring point mutations. We first checked and found the presence of CD45+, F4/80+, and CD11b+ cells both 2 and 4 weeks after B+M tumor induction. This indicates the presence of both adaptive and innate immune cells in the B+M tumor microenvironment. We next asked whether checkpoint inhibition will effectively reduce tumor burden in the B+M model. Therefore, we treated B+M mice with either IgG or anti‐PD1 monoclonal antibodies 4 weeks after tumor induction. Tissues were harvested 3.5 weeks after treatment. We found a modest 20% reduction in liver weight to body weight ratio, a measure of tumor burden, in B+M mice treated with anti‐PD1 compared to IgG controls. Our results demonstrate that HCCs with missense ꞵ‐catenin mutations do respond albeit marginally to checkpoint inhibitors. In the future, combination of checkpoint inhibitors with other inhibitors will be tested in these models to determine their efficacy in treating ꞵ‐catenin‐mutated HCCs.

There and back again: Intracellular trafficking, release and recycling of matrix metalloproteinases.

Matrix metalloproteinases are a family of zinc-dependent endopeptidases that are involved in a large variety of proteolytic processes in physiological and pathological scenarios, including immune cell surveillance, tissue homeostasis, or tumor cell metastasis. This is based on their ability to cleave a plethora of substrates that include components of the extracellular matrix, but also cell surface-associated and intracellular proteins. Accordingly, a tight regulatory web has evolved that closely regulates spatiotemporal activity of specific MMPs. An often underappreciated mechanism of MMP regulation involves their trafficking to and from specific subcellular sites that require MMP activity only for a certain period. In this review, we focus on the current knowledge of MMP intracellular trafficking, their secretion or surface exposure, as well as their recycling back from the cell surface. We discuss molecular mechanisms that enable these steps, in particular microtubule-dependent motility of vesicles that is driven by molecular motors and directed by vesicle regulatory proteins. Finally, we also point out open questions in the field of MMP motility that may become important in the future.

N6-methyladenosine modification participates in neoplastic immunoregulation and tumorigenesis.

This review aims to provide insight into the role of N6-methyladenosine (m6A) modification in neoplastic immunity and subsequent tumorigenesis. m6A modification, which is catalyzed by methyltransferases, demethylases and reader proteins, has emerged as a widespread regulatory mechanism that controls immune-related gene expression and immune reactions during tumorigenesis. Aberrant m6A modification changes the neoplastic immune response in multiple cancers by regulating immune cell infiltration, tumor-promoting inflammation, immunosuppression, immune surveillance, and antitumor immune responses. m6A modification affects immune cell recruitment and cancer-promoting inflammation in hepatocellular carcinoma (HCC) to alter the progression of HCC. m6A modification has been implicated in the infiltration of immune cells and the activation of immune pathways, changing the proliferation and metastasis of gastric cancer. Immune surveillance and the antitumor immune response in breast cancer were enhanced via m6A modification, which inhibited tumor proliferation. m6A modification participates in neoplastic immunoregulation to influence tumor progression.

A Gut Instinct on Leukaemia: A New Mechanistic Hypothesis for Microbiota-Immune Crosstalk in Disease Progression and Relapse.

Despite significant advances in the treatment of Chronic Myeloid and Acute Lymphoblastic Leukaemia (CML and ALL, respectively), disease progression and relapse remain a major problem. Growing evidence indicates the loss of immune surveillance of residual leukaemic cells as one of the main contributors to disease recurrence and relapse. More recently, there was an appreciation for how the host’s gut microbiota predisposes to relapse given its potent immunomodulatory capacity. This is especially compelling in haematological malignancies where changes in the gut microbiota have been identified after treatment, persisting in some patients for years after the completion of treatment. In this hypothesis-generating review, we discuss the interaction between the gut microbiota and treatment responses, and its capacity to influence the risk of relapse in both CML and ALL We hypothesize that the gut microbiota contributes to the creation of an immunosuppressive microenvironment, which promotes tumour progression and relapse.

Chemokine (C-X-C motif) ligand 1 maintains the immune surveillance function of natural killer cells via the PDK2/mTOR signaling pathway.

Chemokine (C-X-C motif) ligand 1 (CXCL1) is mainly expressed on neutrophils and macrophages and has neutrophil chemoattractant activity. However, natural killer (NK) cells also express CXCL1. We were curious about the role played by CXCL1 in NK cells. Knocking out CXCL1 in hematopoietic cells does not affect the occurrence of NK cells; however, it does hinder NK cell maturity. CXCL1 deletion enhances the expression of immature markers and decreases the expression of functional markers in NK cells, which may explain why it hinders the maturation of NK cells. Specific knockout of CXCL1 in NK cells (CXCL1flox/flox Ncr1-cre) leads to impaired IFN-γ production and degranulation of NK cells. The lack of CXCL1 may prevent IFN-γ production and degranulation of NK cells by inhibiting the phosphorylation of AKTS473 and S6. Therefore, we have discovered a new role for CXCL1 in regulating NK cell development and immune surveillance, providing a novel theoretical basis for immunotherapy based on NK cells and potential therapeutic targets for the clinical use of NK cells. 1. Knockout of CXCL1 in hematopoietic cells inhibits the maturation of NK cells. 2. Knockout of CXCL1 in NK cells inhibits the clearance of lymphoma by NK cells and reduces IFN-γ production and CD107 expression in NK cells. 3. CXCL1 activates the PKD2/mTOR signaling pathway, and promotes the production of IFN-γ and the expression of CD107a in NK cells.

IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment.

Breast cancer is the most commonly diagnosed cancer in women. Metastasis is the primary cause of mortality for breast cancer patients. Multiple mechanisms underlie breast cancer metastatic dissemination, including the interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a pleiotropic cytokine that plays an important role in multiple physiological processes including cell proliferation, immune surveillance, acute inflammation, metabolism, and bone remodeling. IL-6 binds to the IL-6 receptor (IL-6Rα) which subsequently binds to the glycoprotein 130 (gp130) receptor creating a signal transducing hexameric receptor complex. Janus kinases (JAKs) are recruited and activated; activated JAKs, in turn, phosphorylate signal transducer and activator of transcription 3 (STAT3) for activation, leading to gene regulation. Constitutively active IL-6/JAK/STAT3 signaling drives cancer cell proliferation and invasiveness while suppressing apoptosis, and STAT3 enhances IL-6 signaling to promote a vicious inflammatory loop. Aberrant expression of IL-6 occurs in multiple cancer types and is associated with poor clinical prognosis and metastasis. In breast cancer, the IL-6 pathway is frequently activated, which can promote breast cancer metastasis while simultaneously suppressing the anti-tumor immune response. Given these important roles in human cancers, multiple components of the IL-6 pathway are promising targets for cancer therapeutics and are currently being evaluated preclinically and clinically for breast cancer. This review covers the current biological understanding of the IL-6 signaling pathway and its impact on breast cancer metastasis, as well as, therapeutic interventions that target components of the IL-6 pathway including: IL-6, IL-6Rα, gp130 receptor, JAKs, and STAT3.

Functional visualization of NK cell-mediated killing of metastatic single tumor cells.

Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is unknown. Here, we have combined ultra-sensitive bioluminescence imaging with intravital two-photon microscopy involving genetically encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hr of arrival, but not thereafter. Intravital dynamic imaging revealed that 50% of NK-tumor cell encounters lead to tumor cell death in the first 4 hr after tumor cell arrival, but after 24 hr of arrival, nearly 100% of the interactions result in the survival of the tumor cell. During this 24-hr period, the probability of ERK activation in NK cells upon encountering the tumor cells was decreased from 68% to 8%, which correlated with the loss of the activating ligand CD155/PVR/Necl5 from the tumor cell surface. Thus, by quantitatively visualizing, the NK-tumor cell interaction at the early stage of metastasis, we have revealed the crucial parameters of NK cell immune surveillance in the lung.

Novel Insights into Genetic Approaches in Glioblastoma Multiforme Therapy

Glioblastoma multiforme is one of the most common and malignant types of central nervous system (CNS) tumors. Despite the great advances in treatment modalities and the variety of therapeutic options, it remains largely incurable with continuously growth incidence, due to the genomic instability of glioblastoma multiforme cells, their heterogeneity, and their resistance to chemo- and radiotherapies. The aggressive behavior of these brain tumors and their sequestered location behind the blood–brain barrier restricts the role of the immune system. Great success has been made recently in glioblastoma multiforme treatment using genetic based approaches to selectively target cancerous cells and restore tumor suppressor gene expression or silence specific oncogenes to prevent their expression. The use of genetic approaches has attracted more interest and research and has revealed their ability to regulate the expression of glioblastoma multiforme oncogenes without changing the genotype and thus avoiding possible genotoxicity. This review delivers an overview of glioblastoma multiforme cell biology, tumorigenesis, and immune surveillance, and discusses recent advances in genetic based therapies of glioblastoma multiforme.

Cancer resistance to immunotherapy: What is the role of cancer stem cells?

Immunotherapy is an emerging form of cancer therapy that is associated with promising outcomes. However, most cancer patients either do not respond to immunotherapy or develop resistance to treatment. The resistance to immunotherapy is poorly understood compared to chemotherapy and radiotherapy. Since immunotherapy targets cells within the tumor microenvironment, understanding the behavior and interactions of different cells within that environment is essential to adequately understand both therapy options and therapy resistance. This review focuses on reviewing and analyzing the special features of cancer stem cells (CSCs), which we believe may contribute to cancer resistance to immunotherapy. The mechanisms are classified into three main categories: mechanisms related to surface markers which are differentially expressed on CSCs and help CSCs escape from immune surveillance and immune cells killing; mechanisms related to CSC-released cytokines which can recruit immune cells and tame hostile immune responses; and mechanisms related to CSC metabolites which modulate the activities of infiltrated immune cells in the tumor microenvironment. This review also discusses progress made in targeting CSCs with immunotherapy and the prospect of developing novel cancer therapies.

The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma.

Simple Summaryγδ T cells play important roles in cancer immunity. Their rapid activation and cytotoxic nature make them promising candidates for use in cell-based immunotherapies; however, under certain conditions, they can induce pro-tumour functions. Furthermore, upon transformation, γδ T cells can develop into aggressive lymphomas with a poor prognosis and no curative therapeutic options. Here, we provide a comprehensive summary of our current knowledge on the complex roles of γδ T cells in cancer. We discuss their anti- and pro-tumour functions in both solid and blood cancers, highlighting the key subsets involved and their potential utility in anti-cancer immunotherapy. We also discuss the mechanisms of γδ T-cell transformation, summarising the resulting γδ T-cell leukaemia/lymphoma entities and their genetic and molecular profiles, as well as current and future treatment strategies.γδ T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional αβ T cells, γδ T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. γδ T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-γ or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, γδ T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of γδ T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of γδ T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of γδ T-cell transformation, summarising the main γδ T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options.

Demographics of PTLD Patients Who Died during 2010-2017 Period: A NCDB Based Study

Background:Post-transplant lymphoproliferative disease (PTLD) is a rare, but well-known complication of solid organ transplants and hematopoietic stem cell transplantation. . In most affected patients, PTLD is an Epstein-Barr virus (EBV)-positive B cell proliferation occurring in the setting of immunosuppression and decreased T cell immune surveillance. PTLDs are among the most serious complications of transplantation. The principal risk factors underlying the development of PTLD are the degree of T cell immunosuppression and the Epstein-Barr virus (EBV) serologic status of the recipient. Early lesions of PTLD are treated with reduction in immunosuppression alone and those who do not have a complete response to this intervention have been treated with chemotherapy, immunotherapy, and occasionally surgical resection. Utilizing the NCDB, we aim to study the clinical and demographic characteristics of PTLD patients who were declared dead during period of 2010-2017.MethodsA total of 425 patients diagnosed with PTLD above the age of 18 years between 2010 and 2017 were identified utilizing the National Cancer Database (NCDB). Patients were identified with ICD-O-3 morphologic code 9971/3 and data extracted from PUF using SPSS. Demographic factors (Race, gender, facility location, annual household income, facility type, Charlson-Deyo score, treatment received, age at diagnosis) were studied in relation to patient's vital status (alive or dead). We have separated data for patients declared dead during this period and formulated a table stating the demographic characteristics. We have excluded people whose vital status was unknown or missing (60 patients).ResultsOf the 365 patients diagnosed with PTLD between 2010-2017, 215 patients were alive during the entire period and 150 (41%) were declared dead in this time frame. Of these, 62.7% were in the age group less than 60 years and 37.3% above 60 years. 9.3% (14/150) received no treatment at all and 88% received some form of treatment, of which 39.3% (59/150) received immunotherapy (34 received immunotherapy alone and 23 received Immuno+chemo). Amongst these, 80% were Caucasians and 13.4% were African Americans. 41.6% (57/137) belonged to median income quartile >=$63,333, whereas 16% (22/137) belonged to median quartile income <$40,227 (Median Quartiles 2012-2016). 83.2% received care at an academic/research program and 8.8% in a Comprehensive community cancer program. 64.7% (97/150) of patient's had Charlson-Deyo score of 0 whereas 14% (21/150) had a score of 3.ConclusionThis study contains largest cohort of patients diagnosed with PTLD, identifying clinical and demographic factors of patients with PTLD who were declared dead during the period of 2010-2017. The data shows significant variations in the populations stratified based on age, income quartiles, treatment received and race. These data may provide insight into identifying the factors influencing mortality of patients diagnosed with PTLD. The major limitations of our study include no data on specific therapy received, reasons for choosing the treatment modality used, no data on the cause of mortality and age at death. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cutaneous immune system: Age specificities

&lt;p&gt;The review is dedicated to the modern concepts in understanding the age-related changes of skin protective functions, with an emphasis on the impairments in interaction between the immune cells of innate and acquired immunity, resulting in a decrease in antigen-specific T cell immune surveillance in the skin. We discuss the various defects of T cells and their environment as well as focus on the issue of possible correction of T-reg and other cells activity in the skin which would increase the level of immune surveillance in elderly persons and reduce the risk of malignant neoplasms or skin infections developing.&lt;/p&gt;

Three-dimensional morphodynamic simulations of macropinocytic cups

SummaryMacropinocytosis refers to the non-specific uptake of extracellular fluid, which plays ubiquitous roles in cell growth, immune surveillance, and virus entry. Despite its widespread occurrence, it remains unclear how its initial cup-shaped plasma membrane extensions form without any external solid support, as opposed to the process of particle uptake during phagocytosis. Here, by developing a computational framework that describes the coupling between the bistable reaction-diffusion processes of active signaling patches and membrane deformation, we demonstrated that the protrusive force localized to the edge of the patches can give rise to a self-enclosing cup structure, without further assumptions of local bending or contraction. Efficient uptake requires a balance among the patch size, magnitude of protrusive force, and cortical tension. Furthermore, our model exhibits cyclic cup formation, coexistence of multiple cups, and cup-splitting, indicating that these complex morphologies self-organize via a common mutually-dependent process of reaction-diffusion and membrane deformation.

How Tim proteins differentially exploit membrane features to attain robust target sensitivity

Immune surveillance cells such as T cells and phagocytes utilize integral plasma membrane receptors to recognize surface signatures on triggered and activated cells such as those in apoptosis. One such family of plasma membrane sensors, the transmembrane immunoglobulin and mucin domain (Tim) proteins, specifically recognize phosphatidylserine (PS) but elicit distinct immunological responses. The molecular basis for the recognition of lipid signals on target cell surfaces is not well understood. Previous results suggest that basic side chains present at the membrane interface on the Tim proteins might facilitate association with additional anionic lipids including but not necessarily limited to PS. We, therefore, performed a comparative quantitative analysis of the binding of the murine Tim1, Tim3, and Tim4, to synthetic anionic phospholipid membranes under physiologically relevant conditions. X-ray reflectivity and vesicle binding studies were used to compare the water-soluble domain of Tim3 with results previously obtained for Tim1 and Tim4. Although a calcium link was essential for all three proteins, the three homologs differed in how they balance the hydrophobic and electrostatic interactions driving membrane association. The proteins also varied in their sensing of phospholipid chain unsaturation and showed different degrees of cooperativity in their dependence on bilayer PS concentration. Surprisingly, trace amounts of anionic phosphatidic acid greatly strengthened the bilayer association of Tim3 and Tim4, but not Tim1. A novel mathematical model provided values for the binding parameters and illuminated the complex interplay among ligands. In conclusion, our results provide a quantitative description of the contrasting selectivity used by three Tim proteins in the recognition of phospholipids presented on target cell surfaces. This paradigm is generally applicable to the analysis of the binding of peripheral proteins to target membranes through the heterotropic cooperative interactions of multiple ligands.

Estrogen markedly reduces circulating low-density neutrophils and enhances pro-tumoral gene expression in neutrophil of tumour-bearing mice

BackgroundNeutrophils are important for immune surveillance of tumour cells. Neutrophils may also be epigenetically programmed in the tumour microenvironment to promote tumour progression. In addition to the commonly known high-density neutrophils (HDN) based on their separation on density gradient, recent studies have reported the presence of high levels of low-density neutrophils (LDN) in tumour-bearing mice and cancer patients. We reported previously that estrogen promotes the growth of estrogen receptor α-negative mammary tumours in mice undergoing mammary involution through stimulating pro-tumoral activities of neutrophils in the mammary tissue.MethodsFemale BALB/cAnNTac mice at 7–8 weeks old were mated and bilateral ovariectomy was performed 2 days post-partum. At 24 h after forced-weaning of pups to induce mammary involution, post-partum female mice were injected with either E2V, or vehicle control on alternative days for 2-weeks. On 48 h post-weaning, treated female mice were inoculated subcutaneously with 4 T1-Luc2 cells into the 9th abdominal mammary gland. Age-matched nulliparous female was treated similarly. Animals were euthanized on day 14 post-tumour inoculation for analysis. To evaluate the short-term effect of estrogen, post-partum females were treated with only one dose of E2V on day 12 post-tumour inoculation.ResultsEstrogen treatment for 2-weeks reduces the number of blood LDN by more than 10-fold in tumour-bearing nulliparous and involuting mice, whilst it had no significant effect on blood HDN. The effect on tumour-bearing mice is associated with reduced number of mitotic neutrophils in the bone marrow and increased apoptosis in blood neutrophils. Since estrogen enhanced tumour growth in involuting mice, but not in nulliparous mice, we assessed the effect of estrogen on the gene expression associated with pro-tumoral activities of neutrophils. Whilst 48 h treatment with estrogen had no effect, 2-weeks treatment significantly increased the expression of Arg1, Il1b and Tgfb1 in both HDN and LDN of involuting mice. In contrast, estrogen increased the expression of Arg1 and Ccl5 in HDN and LDN of nulliparous mice.ConclusionsProlonged estrogenic stimulation in tumour-bearing mice markedly hampered tumour-associated increase of LDN plausibly by inhibiting their output from the bone marrow and by shortening their life span. Estrogen also alters the gene expression in neutrophils that is not seen in tumour-free mice. The results imply that estrogen may significantly influence the tumour-modulating activity of blood neutrophils.