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Clinical and Translational Medicine Aug 2023Gastric cancer (GC) is a malignant tumour, with high morbidity and mortality rates worldwide. The occurrence and development of GC is a complex process involving genetic... (Review)
Review
BACKGROUND
Gastric cancer (GC) is a malignant tumour, with high morbidity and mortality rates worldwide. The occurrence and development of GC is a complex process involving genetic changes in tumour cells and the influence of the surrounding tumour microenvironment (TME). Accumulative evidence shows that tumour-associated macrophages (TAMs) play a vital role in GC, acting as plentiful and active infiltrating inflammatory cells in the TME.
MAIN BODY
In this review, the different functions and mechanisms of TAMs in GC progression, including the conversion of phenotypic subtypes; promotion of tumour proliferation, invasion and migration; induction of chemoresistance; promotion of angiogenesis; modulation of immunosuppression; reprogramming of metabolism; and interaction with the microbial community are summarised. Although the role of TAMs in GC remains controversial in clinical settings, clarifying their significance in the treatment selection and prognostic prediction of GC could support optimising TAM-centred clinicaltherapy.
CONCLUSION
In summary, we reviewed the the phenotypic polarisation, function and molecular mechanism of TAMs and their potential applications in the treatment selection and prognostic prediction of GC.
Topics: Humans; Stomach Neoplasms; Tumor-Associated Macrophages; Immunosuppression Therapy; Microbiota; Tumor Microenvironment
PubMed: 37608500
DOI: 10.1002/ctm2.1386 -
Molecular Cancer Jul 2023Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized... (Review)
Review
Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, allowing neoplastic cells to grow locally and metastasize distantly. The metastatic cells escaping the host immune surveillance are unique in molecular, immunological, and metabolic characteristics. Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. The metastatic immune microenvironment differs from primary tumors in stromal and immune cell composition, functionality, and metabolism. Thus far, multiple molecular and metabolic pathways, distinct from primary tumors, have been identified that dampen immune effector functions, confounding the immunotherapy response in metastatic PDAC. This review describes major immunoregulatory pathways that contribute to the metastatic progression and limit immunotherapy outcomes in PDAC. Overall, we highlight the therapeutic vulnerabilities attributable to immunosuppressive factors and discuss whether targeting these molecular and immunological "hot spots" could improve the outcomes of PDAC immunotherapies.
Topics: Humans; Immunosuppression Therapy; Pancreatic Neoplasms; Adenocarcinoma; Immunotherapy; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed: 37488598
DOI: 10.1186/s12943-023-01813-y -
Nature Reviews. Nephrology Sep 2023Regulatory T (T) cells that express the transcription factor forkhead box protein P3 (FOXP3) are naturally present in the immune system and have roles in the maintenance... (Review)
Review
Regulatory T (T) cells that express the transcription factor forkhead box protein P3 (FOXP3) are naturally present in the immune system and have roles in the maintenance of immunological self-tolerance and immune system and tissue homeostasis. T cells suppress T cell activation, expansion and effector functions by various mechanisms, particularly by controlling the functions of antigen-presenting cells. They can also contribute to tissue repair by suppressing inflammation and facilitating tissue regeneration, for example, via the production of growth factors and the promotion of stem cell differentiation and proliferation. Monogenic anomalies of T cells and genetic variations of T cell functional molecules can cause or predispose patients to the development of autoimmune diseases and other inflammatory disorders, including kidney diseases. T cells can potentially be utilized or targeted to treat immunological diseases and establish transplantation tolerance, for example, by expanding natural T cells in vivo using IL-2 or small molecules or by expanding them in vitro for adoptive T cell therapy. Efforts are also being made to convert antigen-specific conventional T cells into T cells and to generate chimeric antigen receptor T cells from natural T cells for adoptive T cell therapies with the aim of achieving antigen-specific immune suppression and tolerance in the clinic.
Topics: Humans; T-Lymphocytes, Regulatory; Autoimmune Diseases; Immune Tolerance; Immunosuppression Therapy; Kidney Diseases
PubMed: 37400628
DOI: 10.1038/s41581-023-00733-w -
Clinical Journal of the American... Sep 2023The efficacy of immunosuppression in the management of immunoglobulin A (IgA) nephropathy remains highly controversial. The study was conducted to assess the effect of...
BACKGROUND
The efficacy of immunosuppression in the management of immunoglobulin A (IgA) nephropathy remains highly controversial. The study was conducted to assess the effect of immunosuppression, compared with supportive care, in the real-world setting of IgA nephropathy.
METHODS
A cohort of 3946 patients with IgA nephropathy, including 1973 new users of immunosuppressive agents and 1973 propensity score-matched recipients of supportive care, in a nationwide register data from January 2019 to May 2022 in China was analyzed. The primary outcome was a composite of 40% eGFR decrease of the baseline, kidney failure, and all-cause mortality. A Cox proportional hazard model was used to estimate the effects of immunosuppression on the composite outcomes and its components in the propensity score-matched cohort.
RESULTS
Among 3946 individuals (mean [SD] age 36 [10] years, mean [SD] eGFR 85 [28] ml/min per 1.73 m 2 , and mean [SD] proteinuria 1.4 [1.7] g/24 hours), 396 primary composite outcome events were observed, of which 156 (8%) were in the immunosuppression group and 240 (12%) in the supportive care group. Compared with supportive care, immunosuppression treatment was associated with 40% lower risk of the primary outcome events (adjusted hazard ratio, 0.60; 95% confidence interval, 0.48 to 0.75). Comparable effect size was observed for glucocorticoid monotherapy and mycophenolate mofetil alone. In the prespecified subgroup analysis, the treatment effects of immunosuppression were consistent across ages, sexes, levels of proteinuria, and values of eGFR at baseline. Serious adverse events were more frequent in the immunosuppression group compared with the supportive care group.
CONCLUSIONS
Immunosuppressive therapy, compared with supportive care, was associated with a 40% lower risk of clinically important kidney outcomes in patients with IgA nephropathy.
Topics: Humans; Adult; Glomerulonephritis, IGA; Glomerular Filtration Rate; Kidney; Immunosuppression Therapy; Immunosuppressive Agents; Proteinuria
PubMed: 37314777
DOI: 10.2215/CJN.0000000000000215 -
Immunological Reviews Jan 2024Ferroptosis is a form of iron-dependent regulated cell death characterized by the accumulation of toxic lipid peroxides, particularly in the plasma membrane, leading to... (Review)
Review
Ferroptosis is a form of iron-dependent regulated cell death characterized by the accumulation of toxic lipid peroxides, particularly in the plasma membrane, leading to lytic cell death. While it plays a crucial role in maintaining the overall health and proper functioning of multicellular organisms, it can also contribute to tissue damage and pathological conditions. Although ferroptotic damage is generally recognized as an immunostimulatory process associated with the release of damage-associated molecular patterns (DAMPs), the occurrence of ferroptosis in immune cells or the release of immunosuppressive molecules can result in immune tolerance. Consequently, there is ongoing exploration of targeting the upstream signals or the machinery of ferroptosis to therapeutically enhance or inhibit the immune response. In addition to introducing the core molecular mechanisms of ferroptosis, we will focus on the immune characteristics of ferroptosis in pathological conditions, particularly in the context of infection, sterile inflammation, and tumor immunity.
Topics: Humans; Ferroptosis; Cell Death; Immune Tolerance; Immunosuppression Therapy; Immunization
PubMed: 37424139
DOI: 10.1111/imr.13235 -
Journal For Immunotherapy of Cancer Aug 2023Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop...
BACKGROUND
Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop acquired resistance due to the existence of abundant immunosuppressive cells. Tumor-associated macrophages (TAMs), as the dominant immunosuppressive population, impede the antitumor immune response; however, the underlying mechanisms have not been fully elucidated yet.
METHODS
Single-cell RNA sequencing analysis was performed to portray macrophage landscape and revealed the underlying mechanism of component 1q (C1q) TAMs. Malignant pleural effusion (MPE) of human and mouse was used to explore the phenotypes and functions of C1q TAMs.
RESULTS
C1q TAMs highly expressed multiple inhibitory molecules and their high infiltration was significantly correlated with poor prognosis. C1q TAMs promote MPE immunosuppression through impairing the antitumor effects of CD8 T cells. Mechanistically, C1q TAMs enhance fatty acid binding protein 5 (FABP5)-mediated fatty acid metabolism, which activate transcription factor peroxisome proliferator-activated receptor-gamma, increasing the gene expression of inhibitory molecules. A high-fat diet increases the expression of inhibitory molecules in C1q TAMs and the immunosuppression of MPE microenvironment, whereas a low-fat diet ameliorates these effects. Moreover, FABP5 inhibition represses the expression of inhibitory molecules in TAMs and tumor progression, while enhancing the efficacy of ICB therapy in MPE and lung cancer.
CONCLUSIONS
C1q TAMs impede antitumor effects of CD8 T cells promoting MPE immunosuppression. Targeting C1q TAMs effectively alleviates the immunosuppression and enhances the efficacy of ICB therapy. C1q TAMs subset has great potential to be a therapeutic target for cancer immunotherapy.
Topics: Humans; Animals; Mice; Complement C1q; Pleural Effusion, Malignant; Tumor-Associated Macrophages; CD8-Positive T-Lymphocytes; Immunosuppression Therapy; Immunosuppressive Agents; Tumor Microenvironment; Fatty Acid-Binding Proteins
PubMed: 37604643
DOI: 10.1136/jitc-2023-007441 -
Cancer Research Aug 2023Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with a low 5-year survival rate. PDAC is characterized by infiltration of abundant tumor-associated...
UNLABELLED
Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with a low 5-year survival rate. PDAC is characterized by infiltration of abundant tumor-associated macrophages (TAM), which promote immune tolerance and immunotherapeutic resistance. Here we report that macrophage spleen tyrosine kinase (Syk) promotes PDAC growth and metastasis. In orthotopic PDAC mouse models, genetic deletion of myeloid Syk reprogrammed macrophages into immunostimulatory phenotype, increased the infiltration, proliferation, and cytotoxicity of CD8+ T cells, and repressed PDAC growth and metastasis. Furthermore, gemcitabine (Gem) treatment induced an immunosuppressive microenvironment in PDAC by promoting protumorigenic polarization of macrophages. In contrast, treatment with the FDA-approved Syk inhibitor R788 (fostamatinib) remodeled the tumor immune microenvironment, "re-educated" protumorigenic macrophages towards an immunostimulatory phenotype and boosted CD8+ T-cell responses in Gem-treated PDAC in orthotopic mouse models and an ex vivo human pancreatic slice culture model. These findings illustrate the potential of Syk inhibition for enhancing the antitumor immune responses in PDAC and support the clinical evaluation of R788 either alone or together with Gem as a potential treatment strategy for PDAC.
SIGNIFICANCE
Syk blockade induces macrophage polarization to an immunostimulatory phenotype, which enhances CD8+ T-cell responses and improves gemcitabine efficacy in pancreatic ductal adenocarcinoma, a clinically challenging malignancy.
Topics: Mice; Animals; Humans; Gemcitabine; Tumor-Associated Macrophages; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Immune Tolerance; Immunosuppression Therapy; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37306759
DOI: 10.1158/0008-5472.CAN-22-3645 -
International Journal of Hematology Mar 2024Acquired aplastic anemia (AA) in children is a rare bone marrow failure that requires several special considerations for its diagnosis and treatment compared with that... (Review)
Review
Acquired aplastic anemia (AA) in children is a rare bone marrow failure that requires several special considerations for its diagnosis and treatment compared with that in adults. The most common issue is the differential diagnosis with refractory cytopenia of childhood and inherited bone marrow failure syndromes, which is crucial for making decisions on the appropriate treatment for pediatric AA. In addition to detailed morphological evaluation, a comprehensive diagnostic work-up that includes genetic analysis using next-generation sequencing will play an increasingly important role in identifying the underlying etiology of pediatric AA. When discussing treatment strategies for children with acquired AA, the long-term sequelae and level of hematopoietic recovery that affect daily or school life should also be considered, although the overall survival rate has reached 90% after immunosuppressive therapy or hematopoietic cell transplantation (HCT). Recent advances in HCT for pediatric patients with acquired AA have been remarkable, with the successful use of upfront bone marrow transplantation from a matched unrelated donor, unrelated cord blood transplantation or haploidentical HCT as salvage treatment, and fludarabine/melphalan-based conditioning regimens. This review discusses current clinical practices in the diagnosis and treatment of acquired AA in children based on the latest data.
Topics: Adult; Child; Humans; Anemia, Aplastic; Bone Marrow Transplantation; Hematopoietic Stem Cell Transplantation; Pancytopenia; Immunosuppression Therapy; Transplantation Conditioning
PubMed: 36867357
DOI: 10.1007/s12185-023-03564-4 -
Gut Aug 2023Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we...
OBJECTIVE
Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB.
DESIGN
We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models.
RESULTS
We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1 T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1 T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1 T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1 T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models.
CONCLUSION
Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.
Topics: Mice; Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Leukocytes, Mononuclear; Immunosuppression Therapy; Immune Tolerance; Immunotherapy; Nivolumab; CD8-Positive T-Lymphocytes
PubMed: 36450387
DOI: 10.1136/gutjnl-2022-327133 -
Science Translational Medicine Jan 2024Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)...
Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the immune defects that predispose an individual to persistent coronavirus disease 2019 (COVID-19) remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. The median times to nasal viral RNA and culture clearance in individuals with severe immunosuppression due to hematologic malignancy or transplant (S-HT) were 72 and 40 days, respectively, both of which were significantly longer than clearance rates in individuals with severe immunosuppression due to autoimmunity or B cell deficiency (S-A), individuals with nonsevere immunodeficiency, and nonimmunocompromised groups ( < 0.01). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and a higher risk of developing resistance against therapeutic monoclonal antibodies. Both S-HT and S-A participants had diminished SARS-CoV-2-specific humoral responses, whereas only the S-HT group had reduced T cell-mediated responses. This highlights the varied risk of persistent COVID-19 across distinct immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection.
Topics: Humans; SARS-CoV-2; COVID-19; Prospective Studies; Kinetics; Immunosuppression Therapy
PubMed: 38266109
DOI: 10.1126/scitranslmed.adk1599