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1.
J Innate Immun ; 16(1): 143-158, 2024.
Article in English | MEDLINE | ID: mdl-38310854

ABSTRACT

BACKGROUND: Upon infection, mucosal tissues activate a brisk inflammatory response to clear the pathogen, i.e., resistance to disease. Resistance to disease is orchestrated by tissue-resident macrophages, which undergo profound metabolic reprogramming after sensing the pathogen. These metabolically activated macrophages release many inflammatory factors, which promote their bactericidal function. However, in immunocompetent individuals, pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella evade this type of immunity, generating communities that thrive for the long term. SUMMARY: These organisms develop features that render them less susceptible to eradication, such as biofilms and increased tolerance to antibiotics. Furthermore, after antibiotic therapy withdrawal, "persister" cells rapidly upsurge, triggering inflammatory relapses that worsen host health. How these pathogens persisted in inflamed tissues replete with activated macrophages remains poorly understood. KEY MESSAGES: In this review, we discuss recent findings indicating that the ability of P. aeruginosa, S. aureus, and Salmonella to evolve biofilms and antibiotic tolerance is promoted by the similar metabolic routes that regulate macrophage metabolic reprogramming.


Subject(s)
Anti-Bacterial Agents , Biofilms , Macrophages , Biofilms/drug effects , Humans , Animals , Macrophages/immunology , Macrophages/microbiology , Anti-Bacterial Agents/pharmacology , Bacterial Infections/immunology , Pseudomonas aeruginosa/immunology , Pseudomonas aeruginosa/physiology , Staphylococcus aureus/immunology , Staphylococcus aureus/physiology , Drug Resistance, Bacterial , Immune Evasion
2.
Front Immunol ; 14: 1100520, 2023.
Article in English | MEDLINE | ID: mdl-37051229

ABSTRACT

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, the responses to ICI treatment are highly variable in different individuals and the underlying mechanisms remain poorly understood. Here, we employed a mouse squamous cell carcinoma (SCC) model where tumor-bearing recipients diverged into responders (R) versus non-responders (NR) upon anti-PD-L1 treatment. We performed in-depth TCRß sequencing with immunoSEQ platform to delineate the differences in CD8 tumor-infiltrating lymphocytes (TILs). We found that R and NR CD8 TILs both exhibited evidence of clonal expansion, suggesting activation regardless of response status. We detected no differences in clonal expansion or clonal diversity indexes between R vs. NR. However, the top expanded (>1%) TCRß clonotypes appeared to be mutually exclusive between R and NR CD8 TILs, showing a preferential expansion of distinct TCRß clonotypes in response to the same SCC tumor in R vs. NR. Notably, the mutual exclusivity of TCR clonotypes in R vs. NR was only observed when top TCRß clonotypes were counted, because such top-expanded clonotypes are present in the opposite outcome group at a much lower frequency. Many TCRß sequences were detected in only one recipient at a high frequency, implicating highly individualized anti-tumor immune responses. We conclude that differences in the clonal frequency of top TCR clonotypes between R and NR CD8 TILs may be one of the factors underlying differential anti-PD-L1 responses. This notion may offer a novel explanation for variable ICI responses in different individuals, which may substantially impact the development of new strategies for personalized cancer immunotherapy.


Subject(s)
CD8-Positive T-Lymphocytes , Immunotherapy , Animals , Mice , Receptors, Antigen, T-Cell
3.
Eur J Surg Oncol ; 49(4): 709-715, 2023 04.
Article in English | MEDLINE | ID: mdl-36764880

ABSTRACT

BACKGROUND: De-escalation of axillary surgery for lymph node (LN) positive breast cancer is facilitated by marking involved nodes which, when removed with sentinel nodes constitute risk-adapted targeted axillary dissection (TAD). Whether after chemotherapy or for primary surgery, selected patients with biopsy-proven involvement of nodes may be eligible for axillary conservation. Likewise, impalpable recurrence or stage 4 patients with localised axillary disease may benefit. In these contexts, several devices are used to mark biopsied nodes to facilitate their accurate surgical removal. We report our experience using the paramagnetic MAGSEED (Endomag®, Cambridge, UK). METHODS: Local approval (BR2021_149) was obtained to interrogate a prospective database of all axillary markers. The primary endpoint was successful removal of the marked LN. RESULTS: Of 241 markers (in 221 patients) inserted between October 2018 and July 2022, all were retrieved. Of 74 patients who had Magseeds® inserted after completion of NACT (involved nodes initially marked using an UltraCor™Twirl™ marker), the Magseeds® were found outside the node in neighbouring axillary tissue in 18 (24.3%) patients. When Magseeds® were placed at commencement of NACT in 54 patients, in only 1 (1.8%) was the marker found outside the node - a statistically significantly lower rate (Chi2 10.7581 p = 0.001038). For 'primary TAD' patients and those localised for recurrent or stage IV disease, all 93 had the Magseed® found within the biopsied node. CONCLUSION: This series supports our axillary nodal marking technique as safe and reliable. For TAD following NACT, placement at the start of treatment led to a significantly higher localisation rate.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/pathology , Sentinel Lymph Node Biopsy/methods , Neoadjuvant Therapy/methods , Lymph Nodes/surgery , Lymph Nodes/pathology , Lymph Node Excision/methods , Lymphatic Metastasis/pathology , Axilla/pathology , Neoplasm Staging
4.
ANZ J Surg ; 93(1-2): 344-345, 2023 01.
Article in English | MEDLINE | ID: mdl-35460151

Subject(s)
Breast , Humans , Biopsy
5.
Front Immunol ; 13: 992630, 2022.
Article in English | MEDLINE | ID: mdl-36330507

ABSTRACT

Differential responses to immune checkpoint inhibitors (ICI) may be attributed to tumor-intrinsic factors or environmental cues; however, these mechanisms cannot fully explain the variable ICI responses in different individuals. Here, we investigate the potential contribution of immunological heterogeneity with a focus on differences in T-cell receptor (TCR) repertoire to ICI responses, which has not been defined previously. To reveal additional factors underlying heterogeneous responses to ICI, we employed a squamous cell carcinoma (SCC) mouse model in which tumor-bearing recipients unambiguously diverged into responders (R) or non-responders (NR) upon anti-PD-L1 treatment. Treatment efficacy absolutely required CD8 T-cells and correlated positively with effector functions of CD8 tumor-infiltrating lymphocytes (TILs). We showed that TCR repertoires exhibited a similar magnitude of clonal expansion in R vs. NR CD8 TILs. However, the top expanded TCR clonotypes appeared to be mutually exclusive between R and NR CD8 TILs, which also occurred in a recipient-specific manner, demonstrating preferential expansion of distinct TCR clonotypes against the same SCC tumor. Unexpectedly, R vs. NR CD8 TILs reached all activation clusters and did not exhibit substantial global differences in transcriptomes. By linking single-cell transcriptomic data with unique TCR clonotypes, CD8 TILs harboring top TCR clonotypes were found to occupy distinct activation clusters and upregulate genes favoring anti-tumor immunity to different extents in R vs. NR. We conclude that stochastic differences in CD8 TIL TCR repertoire and distinct activation states of top TCR clonotypes may contribute to differential anti-PD-L1 responses. Our study suggests that host-intrinsic immunological heterogeneity may offer a new explanation for differential ICI responses in different individuals, which could impact on strategies for personalized cancer immunotherapy.


Subject(s)
Carcinoma, Squamous Cell , Lymphocytes, Tumor-Infiltrating , Mice , Animals , CD8-Positive T-Lymphocytes , Lymphocyte Activation , Receptors, Antigen, T-Cell/genetics
6.
J Med Imaging Radiat Oncol ; 66(8): 1084-1086, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35916441

ABSTRACT

Schistosomiasis is prevalent in some developing countries; however, it does not commonly affect the breast. Mammary schistosomiasis may present as suspicious microcalcification or a mass on mammography. Image-guided biopsy is necessary to exclude malignancy and identify calcified Schistosoma ova on histology. We report a case of a patient born in the Philippines who was diagnosed with mammary schistosomiasis from incidental microcalcifications seen on mammography.


Subject(s)
Breast Diseases , Breast Neoplasms , Calcinosis , Schistosomiasis , Humans , Female , Breast/pathology , Breast Diseases/diagnostic imaging , Breast Diseases/pathology , Mammography , Schistosomiasis/complications , Schistosomiasis/diagnostic imaging , Breast Neoplasms/pathology
7.
J Exp Clin Cancer Res ; 41(1): 123, 2022 Apr 02.
Article in English | MEDLINE | ID: mdl-35366939

ABSTRACT

BACKGROUND: While immune checkpoint inhibitors (ICI) were approved for head and neck squamous cell carcinomas (HNSCCs), the response rate remains relatively low. Mechanisms underlying ICI unresponsiveness versus sensitivity are not fully understood. METHOD: To better delineate differential responses to ICI treatment, we employed mouse SCC models, termed KPPA tumors that were caused by deleting p53 and hyperactivating PIK3CA, two most frequently mutated genes in human HNSCCs. We transplanted two KPPA tumor lines (TAb2 versus TCh3) into C57BL/6 recipients and examined the immune tumor microenvironment using flow cytometry. Furthermore, we employed single-cell RNA sequencing to identify the difference in tumor infiltrating lymphocytes (TILs). RESULTS: We found that different KPPA tumors exhibited heterogeneous immune profiles pre-existing treatment that dictated their sensitivity or unresponsiveness to anti-PD-L1. Unresponsive TAb2 tumors were highly enriched with functional tumor-associated macrophages (TAMs), especially M2-TAMs. In contrast, sensitive TCh3 tumors contained more CD8 TILs with better effector functions. TAb2 tumor cells drastically expanded F4/80+ TAMs from bone marrow precursors, requiring CSF1 and VEGF. Consistently, a higher combined expression of VEGF-C and CSF1 predicts worse survival in PIK3CAAmp/TP53Mutated HNSCC patients. Unresponsive TAb2 tumors upregulated distinct signaling pathways that correlate with aggressive tumor phenotypes. While anti-PD-L1 did not affect the TME of TAb2 tumors, it significantly increased the number of CD8 TILs in TCh3 tumors. CONCLUSIONS: We uncovered tumor-intrinsic differences that may underlie the differential responses to ICI by establishing and employing two SCC tumor lines, TAb2 vs. TCh3, both of which harbor TP53 deletion and PIK3CA hyperactivation. Our study indicates the limitation of stratifying cancers according to their genetic alterations and suggests that evaluating HNSCC tumor-intrinsic cues along with immune profiles in the TME may help better predict ICI responses. Our experimental models may provide a platform for pinpointing tumor-intrinsic differences underlying an immunosuppressive TME in HNSCCs and for testing combined immunotherapies targeting either tumor-specific or TAM-specific players to improve ICI efficacy.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Animals , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Humans , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Mice , Mice, Inbred C57BL , Oncogenes , Tumor Microenvironment
8.
J Virol ; 96(7): e0216121, 2022 04 13.
Article in English | MEDLINE | ID: mdl-35297660

ABSTRACT

Vaccine-induced protective T cell immunity is necessary for HIV-1 functional cure. We previously reported that rhesus PD1-Gag-based DNA vaccination sustained simian-human immunodeficiency virus (SHIV) suppression by inducing effector-memory CD8+ T cells. Here, we investigated a human PD1-Gag-based DNA vaccine, namely, ICVAX, for clinical translation. PD1-based dendritic cell targeting and mosaic antigenic designs were combined to generate the ICVAX by fusing the human soluble PD1 domain with a bivalent HIV-1 Gag-p41 mosaic antigen. The mosaic antigen was cross-reactive with patients infected with B, CRF07/08_BC, and CRF01_AE variants. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses than mosaic Gag-p41 alone, and suppressed EcoHIV infection more efficiently. In macaques, ICVAX elicited polyfunctional effector-memory T cell responses that targeted multiple nonoverlapping epitopes of the Gag-p41 antigen. Furthermore, ICVAX manufactured following good manufacturing practices proved potent immunogenicity in macaques after biannual homologous vaccination, warranting clinical evaluation of ICVAX as an immunotherapy against HIV-1. IMPORTANCE This study presents that ICVAX, a PD1-based DNA vaccine against HIV-1, could induce broad and polyfunctional T cell responses against different HIV-1 subtypes. ICVAX encodes a recombinant antigen consisting of the human soluble PD1 domain fused with two mosaic Gag-p41 antigens. The mosaic antigens cover more than 500 HIV-1 strains circulating in China including the subtypes B/B', CRF01_AE, and CRF07/08_BC. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses, with better EcoHIV suppression than the nontargeting mosaic Gag-p41 DNA vaccine. Moreover, both lab-generated and GMP-grade ICVAX also elicited strong polyfunctional effector-memory T cell responses in rhesus macaques with good immunogenicity against multiple nonoverlapping epitopes of the Gag-p41 antigen. This study therefore highlights the great potential to translate the PD1-based DNA vaccine approach into clinical use, and opens up new avenues for alternative HIV-1 vaccine design for HIV-1 preventive and functional cure.


Subject(s)
HIV Infections , HIV-1 , Vaccines, Combined , Vaccines, DNA , Viral Vaccines , AIDS Vaccines/immunology , Animals , Antigens, Viral , CD48 Antigen , CD8-Positive T-Lymphocytes , Epitopes/immunology , Gene Products, gag/genetics , Gene Products, gag/immunology , HIV Infections/prevention & control , HIV-1/genetics , Humans , Macaca mulatta , Memory T Cells , Mice , Vaccines, Combined/genetics , Vaccines, Combined/immunology , Vaccines, DNA/genetics , Vaccines, DNA/immunology , Viral Vaccines/genetics , Viral Vaccines/immunology
9.
PLoS Pathog ; 17(6): e1009647, 2021 06.
Article in English | MEDLINE | ID: mdl-34125864

ABSTRACT

HIV-1 functional cure requires sustained viral suppression without antiretroviral therapy. While effector-memory CD8+ T lymphocytes are essential for viremia control, few vaccines elicit such cellular immunity that could be potently recalled upon viral infection. Here, we investigated a program death-1 (PD1)-based vaccine by fusion of simian immunodeficiency virus capsid antigen to soluble PD1. Homologous vaccinations suppressed setpoint viremia to undetectable levels in vaccinated macaques following a high-dose intravenous challenge by the pathogenic SHIVSF162P3CN. Poly-functional effector-memory CD8+ T cells were not only induced after vaccination, but were also recalled upon viral challenge for viremia control as determined by CD8 depletion. Vaccine-induced effector memory CD8+ subsets displayed high cytotoxicity-related genes by single-cell analysis. Vaccinees with sustained viremia suppression for over two years responded to boost vaccination without viral rebound. These results demonstrated that PD1-based vaccine-induced effector-memory CD8+ T cells were recalled by AIDS virus infection, providing a potential immunotherapy for functional cure.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , Programmed Cell Death 1 Receptor/immunology , SAIDS Vaccines/immunology , Viremia/prevention & control , Animals , Female , Macaca mulatta , Mice , Mice, Inbred C57BL , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Immunodeficiency Virus , Vaccines, DNA/immunology , gag Gene Products, Human Immunodeficiency Virus/immunology
10.
J Immunother Cancer ; 9(1)2021 01.
Article in English | MEDLINE | ID: mdl-33414263

ABSTRACT

BACKGROUND: Antitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences. METHODS: We developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes. RESULTS: We discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRß sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status. CONCLUSIONS: We reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Gene Expression Profiling/methods , Head and Neck Neoplasms/genetics , Lymphocytes, Tumor-Infiltrating/immunology , Receptors, Antigen, T-Cell/genetics , Sequence Analysis, DNA/methods , Squamous Cell Carcinoma of Head and Neck/genetics , Animals , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Genotype , Head and Neck Neoplasms/immunology , Humans , Lymphocyte Activation , Male , Mice , Neoplasm Transplantation , Sequence Analysis, RNA , Single-Cell Analysis/methods , Squamous Cell Carcinoma of Head and Neck/immunology , Tumor Microenvironment
11.
Cell Mol Immunol ; 18(3): 723-734, 2021 03.
Article in English | MEDLINE | ID: mdl-32427883

ABSTRACT

Cancer cells can evade immune recognition by losing major histocompatibility complex (MHC) class I. Hence, MHC class I-negative cancers represent the most challenging cancers to treat. Chemotherapeutic drugs not only directly kill tumors but also modulate the tumor immune microenvironment. However, it remains unknown whether chemotherapy-treated cancer cells can activate CD8 T cells independent of tumor-derived MHC class I and whether such MHC class I-independent CD8 T-cell activation can be exploited for cancer immunotherapy. Here, we showed that chemotherapy-treated cancer cells directly activated CD8 T cells in an MHC class I-independent manner and that these activated CD8 T cells exhibit virtual memory (VM) phenotypes. Consistently, in vivo chemotherapeutic treatment preferentially increased tumor-infiltrating VM CD8 T cells. Mechanistically, MHC class I-independent activation of CD8 T cells requires cell-cell contact and activation of the PI3K pathway. VM CD8 T cells contribute to a superior therapeutic effect on MHC class I-deficient tumors. Using humanized mouse models or primary human CD8 T cells, we also demonstrated that chemotherapy-treated human lymphomas activated VM CD8 T cells independent of tumor-derived MHC class I. In conclusion, CD8 T cells can be directly activated in an MHC class I-independent manner by chemotherapy-treated cancers, and these activated CD8 T cells may be exploited for developing new strategies to treat MHC class I-deficient cancers.


Subject(s)
Antigen Presentation/immunology , Antineoplastic Agents/pharmacology , CD8-Positive T-Lymphocytes/immunology , Colonic Neoplasms/immunology , Histocompatibility Antigens Class I/immunology , Lymphoma/immunology , Memory T Cells/immunology , Animals , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Lymphocyte Activation/immunology , Lymphoma/drug therapy , Lymphoma/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Tumor Microenvironment
12.
Int J Mol Sci ; 21(18)2020 Sep 09.
Article in English | MEDLINE | ID: mdl-32916850

ABSTRACT

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs.


Subject(s)
Carcinoma, Squamous Cell/etiology , Class I Phosphatidylinositol 3-Kinases/metabolism , Genes, p53 , Head and Neck Neoplasms/etiology , Keratin-15/metabolism , Animals , Carcinoma, Squamous Cell/mortality , Class I Phosphatidylinositol 3-Kinases/genetics , Head and Neck Neoplasms/mortality , Humans , Lymphocytes, Tumor-Infiltrating , Mice, Transgenic , Neoplasms, Experimental , Tumor Microenvironment
13.
Sci Rep ; 10(1): 15511, 2020 09 23.
Article in English | MEDLINE | ID: mdl-32968182

ABSTRACT

Osmolytes are organic solutes that change the protein folding landscape shifting the equilibrium towards the folded state. Herein, we use osmolytes to probe the structuring and aggregation of the intrinsically disordered mutant Huntingtin (mHtt) vis-a-vis the pathogenicity of mHtt on transcription factor function and cell survival. Using an inducible PC12 cell model of Huntington's disease (HD), we show that stabilizing polyol osmolytes drive the aggregation of Htt103QExon1-EGFP from a diffuse ensemble into inclusion bodies (IBs), whereas the destabilizing osmolyte urea does not. This effect of stabilizing osmolytes is innate, generic, countered by urea, and unaffected by HSP70 and HSC70 knockdown. A qualitatively similar result of osmolyte-induced mHtt IB formation is observed in a conditionally immortalized striatal neuron model of HD, and IB formation correlates with improved survival under stress. Increased expression of diffuse mHtt sequesters the CREB transcription factor to repress CREB-reporter gene activity. This repression is mitigated either by stabilizing osmolytes, which deplete diffuse mHtt or by urea, which negates protein-protein interaction. Our results show that stabilizing polyol osmolytes promote mHtt aggregation, alleviate CREB dysfunction, and promote survival under stress to support the hypothesis that lower molecular weight entities of disease protein are relevant pathogenic species in neurodegeneration.


Subject(s)
Cyclic AMP Response Element-Binding Protein/metabolism , Huntingtin Protein/metabolism , Huntington Disease/metabolism , Animals , Autophagy , Gene Knockdown Techniques , Glycerol/pharmacology , HSC70 Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/metabolism , Huntingtin Protein/genetics , Mutation , Osmolar Concentration , PC12 Cells , Protein Aggregation, Pathological/genetics , Protein Aggregation, Pathological/metabolism , Protein Folding , Rats , Sorbitol/pharmacology , Sucrose/pharmacology , Trehalose/pharmacology
14.
Nature ; 585(7824): 261-267, 2020 09.
Article in English | MEDLINE | ID: mdl-32848246

ABSTRACT

Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent viral reservoir1. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation2,3, may be feasible in rare instances.


Subject(s)
Gene Silencing , HIV Infections/genetics , HIV Infections/virology , HIV-1/genetics , Heterochromatin/genetics , Proviruses/genetics , Virus Integration/genetics , Virus Latency/genetics , Adult , Aged , Centromere/genetics , Chromosomes, Human, Pair 19/genetics , DNA, Satellite/genetics , Female , Genome, Viral/genetics , HIV Infections/blood , HIV-1/isolation & purification , Heterochromatin/metabolism , Humans , Male , Middle Aged , Proviruses/isolation & purification , Repressor Proteins/genetics , Transcription Initiation Site
15.
J Immunol ; 205(3): 830-841, 2020 08 01.
Article in English | MEDLINE | ID: mdl-32591397

ABSTRACT

The BCR recognizes foreign Ags to initiate humoral immunity that needs isotype-switched Abs generated via class switch recombination (CSR); however, stimulating the BCR in the absence of costimulation (e.g., CD40) does not induce CSR; thus, it remains elusive whether and how the BCR induces CSR mechanistically. Autoreactive B cells can maintain anergy via unresponsiveness of their BCRs to self-antigens. However, it remains unknown what molecule(s) restrict BCR signaling strength for licensing BCR-induced CSR and whether deficiency of such molecule(s) disrupts autoreactive B cell anergy and causes B cell-mediated diseases by modulating BCR signaling. In this study, we employ mouse models to show that the BCR's capacity to induce CSR is restrained by B cell-intrinsic checkpoints TRAF3 and TRAF2, whose deletion in B cells enables the BCR to induce CSR in the absence of costimulation. TRAF3 deficiency permits BCR-induced CSR by elevating BCR-proximal signaling intensity. Furthermore, NF-κB2 is required for BCR-induced CSR in TRAF3-deficient B cells but not for CD40-induced or LPS-induced CSR, suggesting that TRAF3 restricts NF-κB2 activation to specifically limit the BCR's ability to induce CSR. TRAF3 deficiency also disrupts autoreactive B cell anergy by elevating calcium influx in response to BCR stimulation, leading to lymphoid organ disorders and autoimmune manifestations. We showed that TRAF3 deficiency-associated autoimmune phenotypes can be rectified by limiting BCR repertoires or attenuating BCR signaling strength. Thus, our studies highlight the importance of TRAF3-mediated restraint on BCR signaling strength for controlling CSR, B cell homeostasis, and B cell-mediated disorders.


Subject(s)
B-Lymphocytes/immunology , Clonal Anergy , Immunoglobulin Class Switching/immunology , Receptors, Antigen, B-Cell/immunology , Signal Transduction/immunology , TNF Receptor-Associated Factor 3/immunology , Animals , B-Lymphocytes/cytology , Mice , Mice, Transgenic , NF-kappa B p52 Subunit/genetics , NF-kappa B p52 Subunit/immunology , Signal Transduction/genetics , TNF Receptor-Associated Factor 2/genetics , TNF Receptor-Associated Factor 2/immunology , TNF Receptor-Associated Factor 3/genetics
16.
J Biol Rhythms ; 35(5): 465-475, 2020 10.
Article in English | MEDLINE | ID: mdl-32536240

ABSTRACT

The suprachiasmatic nucleus (SCN) drives circadian rhythms in locomotion through coupled, single-cell oscillations. Global genetic deletion of the neuropeptide Vip or its receptor Vipr2 results in profound deficits in daily synchrony among SCN cells and daily rhythms in locomotor behavior and glucocorticoid secretion. To test whether this phenotype depends on vasoactive intestinal polypeptide (VIP) neurons in the SCN, we ablated VIP SCN neurons in vivo in adult male mice through Caspase3-mediated induction of the apoptotic pathway in cre-expressing VIP neurons. We found that ablation of VIP SCN neurons in adult mice caused a phenotype distinct from Vip- and Vipr2-null mice. Mice lacking VIP neurons retained rhythmic locomotor activity with a shortened circadian period, more variable onsets, and decreased duration of daily activity. Circadian hormonal outputs, specifically corticosterone rhythms, were severely dampened. In contrast, deletion of neonatal SCN VIP neurons dramatically reduced circadian gene expression in the cultured SCN, mimicking the effects of global deletion of Vip or Vipr2. These results suggest that SCN VIP neurons play a role in lengthening circadian period and stimulating the daily surge in glucocorticoids in adults and in synchronizing and sustaining daily rhythms among cells in the developing SCN.


Subject(s)
Aging/metabolism , Circadian Clocks , Circadian Rhythm , Neurons/metabolism , Suprachiasmatic Nucleus/metabolism , Vasoactive Intestinal Peptide/metabolism , Animals , Animals, Newborn/metabolism , Circadian Clocks/genetics , Circadian Rhythm/genetics , Glucocorticoids/metabolism , Male , Mice , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism
17.
J Infect Dis ; 222(11): 1837-1842, 2020 11 09.
Article in English | MEDLINE | ID: mdl-32496516

ABSTRACT

AIDS Clinical Trials Group study A5308 found reduced T-cell activation and exhaustion in human immunodeficiency virus (HIV) controllers start antiretroviral therapy (ART). We further assessed HIV-specific T-cell responses and post-ART viral loads. Before ART, the 31% of participants with persistently undetectable viremia had more robust HIV-specific T-cell responses. During ART, significant decreases were observed in a broad range of T-cell responses. Eight controllers in A5308 and the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort showed no viremia above the level of quantification in the first 12 weeks after ART discontinuation. ART significantly reduced HIV-specific T-cell responses in HIV controllers but did not adversely affect controller status after ART discontinuation.


Subject(s)
Anti-Retroviral Agents/therapeutic use , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , T-Lymphocytes/immunology , Adult , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cohort Studies , HIV Protease Inhibitors/therapeutic use , Humans , Lymphocyte Activation/drug effects , Viral Load/drug effects , Viremia/immunology
18.
Asia Pac J Clin Oncol ; 16(6): 348-355, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32573084

ABSTRACT

AIMS: In the Northern Territory (NT) of Australia, Indigenous women have a lower incidence of breast cancer, but a higher mortality than Non-indigenous women. The aim of this study was to describe and compare breast cancer pathological features related to stage and biological aggression between the two groups. METHODS: Subjects were identified by extract from the NT Cancer Registry in two separate cohorts, cohort 1 (1991-2000) and cohort 2 (2001-2010). Data from cohort 1 included age, stage, tumor grade and estrogen receptor status (ER) and treatment completion. Additional pathological variables including tumor size, HER2 status, lymphovascular invasion and derived tumor phenotype were available for cohort 2. Bivariate P values for categoric variables were calculated using Fisher's exact tests.  The Wilcoxon rank-sum test was used to compare cohort 2. Logistic regression was used to calculate odds ratios. RESULTS: There were 359 (44 indigenous) eligible women in cohort 1 and 526 (100 indigenous) for cohort 2. In cohort 1, in both cohorts, indigenous women were more likely to present at an advanced stage, but there was no difference in ER status or tumor grade. When derived phenotypes were compared, indigenous women were less likely to have better prognosis luminal A tumors, and more likely to have HER2-enriched tumors. CONCLUSION: This two decade long comparison of the pathological features of breast cancer between indigenous and nonindigenous women of the NT has confirmed that Indigenous women not only present at a later stage than NI women but are also afflicted by poorer prognosis tumors, particularly HER2 enriched.


Subject(s)
Breast Neoplasms/epidemiology , Aged , Breast Neoplasms/pathology , Cohort Studies , Female , Humans , Incidence , Indigenous Peoples , Middle Aged , Northern Territory/epidemiology , Prognosis , Registries , Retrospective Studies
19.
Protein Cell ; 11(7): 472-482, 2020 07.
Article in English | MEDLINE | ID: mdl-32162275

ABSTRACT

Immunotherapy has been applied successfully to treat B-cell lymphomas in preclinical models or clinical settings. However, immunotherapy resistance is a major challenge for B-cell lymphoma treatment. To overcome this issue, combinatorial therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas. One of such strategies is to combine immunotherapy with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can potentially increase tumor immunogenicity, promote anti-tumor immune responses, or reverse immunosuppressive tumor environments. Thus, the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment. However, not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target. Hence, we suggest that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors. Here, we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.


Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Immunotherapy , Lymphoma, B-Cell/therapy , Humans , Lymphoma, B-Cell/metabolism
20.
Mol Carcinog ; 59(7): 766-774, 2020 07.
Article in English | MEDLINE | ID: mdl-32017286

ABSTRACT

Head and neck cancers are a heterogeneous group of tumors that are highly aggressive and collectively represent the sixth most common cancer worldwide. Ninety percent of head and neck cancers are squamous cell carcinomas (HNSCCs). The tumor microenvironment (TME) of HNSCCs consists of many different subsets of cells that infiltrate the tumors and interact with the tumor cells or with each other through various networks. Both innate and adaptive immune cells play a crucial role in mediating immune surveillance and controlling tumor growth. Here, we discuss the different subsets of immune cells and how they contribute to an immunosuppressive TME of HNSCCs. We also briefly summarize recent advances in immunotherapeutic approaches for HNSCC treatment. A better understanding of the multiple factors that play pivotal roles in HNSCC tumorigenesis and tumor progression may help define novel targets to develop more effective immunotherapies for patients with HNSCC.


Subject(s)
Head and Neck Neoplasms/immunology , Tumor Microenvironment/immunology , Animals , Cell Transformation, Neoplastic/immunology , Head and Neck Neoplasms/therapy , Humans , Immunotherapy/methods , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/therapy
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