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Frontiers in Immunology 2024The past decade has witnessed a revolution in cancer treatment, shifting from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based... (Review)
Review
The past decade has witnessed a revolution in cancer treatment, shifting from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular immune-checkpoint inhibitors (ICIs). These immunotherapies release the host's immune system against the tumor and have shown unprecedented durable remission for patients with cancers that were thought incurable, such as metastatic melanoma, metastatic renal cell carcinoma (RCC), microsatellite instability (MSI) high colorectal cancer and late stages of non-small cell lung cancer (NSCLC). However, about 80% of the patients fail to respond to these immunotherapies and are therefore left with other less effective and potentially toxic treatments. Identifying and understanding the mechanisms that enable cancerous cells to adapt to and eventually overcome therapy can help circumvent resistance and improve treatment. In this review, we describe the recent discoveries on the onco-immunological processes which govern the tumor microenvironment and their impact on the resistance to PD-1/PD-L1 checkpoint blockade.
Topics: Humans; Immune Checkpoint Inhibitors; Drug Resistance, Neoplasm; Tumor Microenvironment; Neoplasms; Animals; Immunotherapy; B7-H1 Antigen; Programmed Cell Death 1 Receptor
PubMed: 38903504
DOI: 10.3389/fimmu.2024.1384121 -
Frontiers in Immunology 2024Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse...
Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse outcomes in multiple human cancers. Within the tumour microenvironment (TME), tumour-associated macrophages (TAMs) promote tumour growth and metastasis, making them prime targets for cancer immunotherapy. Recent single-cell analysis suggest that proliferating TAMs accumulate in human cancers, yet their origins and differentiation pathways remain uncertain. Here, we show that a subpopulation of CD163+ TAMs proliferates within the TME of melanoma, lung cancer, and breast cancer. Consistent with their potential role in suppressing anti-tumour activities of T cells, CD163+ TAMs express a range of potent immunosuppressive molecules, including PD-L1, PD-L2, IL-10, and TGF-β. Other phenotypic markers strongly suggested that these cells originate from CD14+ CCR2+ monocytes, a cell population believed to have minimal capacity for proliferation. However, we demonstrate that certain myelopoietic cytokines commonly available within the TME induce robust proliferation of human monocytes, especially the combination of interleukin 3 (IL-3) and Macrophage Colony-Stimulating Factor 1 (M-CSF). Monocytic cells cultured with these cytokines efficiently modulate T cell proliferation, and their molecular phenotype recapitulates that of CD163+ TAMs. IL-3-driven proliferation of monocytic cells can be completely blocked by IL-4, associated with the induction of CDKN1A, alongside the upregulation of transcription factors linked to dendritic cell function, such as BATF3 and IRF4. Taken together, our work suggests several novel therapeutic routes to reducing immunosuppressive TAMs in human tumours, from blocking chemokine-mediated recruitment of monocytes to blocking their proliferation.
Topics: Humans; Monocytes; Cell Proliferation; Tumor Microenvironment; Tumor-Associated Macrophages; Neoplasms; Antigens, CD; Female; Macrophages; Receptors, Cell Surface; Antigens, Differentiation, Myelomonocytic; Cytokines; T-Lymphocytes; Breast Neoplasms
PubMed: 38903497
DOI: 10.3389/fimmu.2024.1412076 -
Stem Cell Research & Therapy Jun 2024Human hematopoietic stem cell (HSC)-transferred humanized mice are valuable models for exploring human hematology and immunology. However, sufficient recapitulation of...
Human hematopoietic stem cell (HSC)-transferred humanized mice are valuable models for exploring human hematology and immunology. However, sufficient recapitulation of human hematopoiesis in mice requires large quantities of enriched human CD34 HSCs and total-body irradiation for adequate engraftment. Recently, we generated a NOG mouse strain with a point mutation in the c-kit tyrosine kinase domain (W41 mutant; NOGW mice). In this study, we examined the ability of NOGW mice to reconstitute human hematopoietic cells. Irradiated NOGW mice exhibited high engraftment levels of human CD45 cells in the peripheral blood, even when only 5,000-10,000 CD34 HSCs were transferred. Efficient engraftment of human CD45 cells was also observed in non-irradiated NOGW mice transferred with 20,000-40,000 HSCs. The bone marrow (BM) of NOGW mice exhibited significantly more engrafted human HSCs or progenitor cells (CD34CD38 or CD34CD38 cells) than the BM of NOG mice. Furthermore, we generated a human cytokine (interleukin-3 and granulocyte-macrophage colony-stimulating factor) transgenic NOG-W41 (NOGW-EXL) mouse to achieve multilineage reconstitution with sufficient engraftment of human hematopoietic cells. Non-irradiated NOGW-EXL mice showed significantly higher engraftment levels of human CD45 and myeloid lineage cells, particularly granulocytes and platelets/megakaryocytes, than non-irradiated NOGW or irradiated NOG-EXL mice after human CD34 cell transplantation. Serial BM transplantation experiments revealed that NOGW mice exhibited the highest potential for long-term HSC compared with other strains. Consequently, c-kit mutant NOGW-EXL humanized mice represent an advanced model for HSC-transferred humanized mice and hold promise for widespread applications owing to their high versatility.
Topics: Animals; Humans; Proto-Oncogene Proteins c-kit; Hematopoiesis; Mice; Hematopoietic Stem Cells; Hematopoietic Stem Cell Transplantation; Mice, Transgenic; Cell Lineage; Antigens, CD34; Interleukin-3; Mutation
PubMed: 38902833
DOI: 10.1186/s13287-024-03799-w -
Scientific Reports Jun 2024Acute myeloid leukaemia (AML) is an aggressive leukaemia characterised by uncontrolled blast cell proliferation. miRNAs and Clusters of Differentiation (CD) molecules...
Acute myeloid leukaemia (AML) is an aggressive leukaemia characterised by uncontrolled blast cell proliferation. miRNAs and Clusters of Differentiation (CD) molecules play essential roles in AML progression. This study aims to investigate the effect of COVID-19 on the expression of circulating miRNA and CD molecules in AML. This cross-sectional study recruited 32 AML patients and 20 controls. Blood samples were collected and analysed using molecular cytogenetic, miRNA/mRNA expression, and flow cytometry techniques. The expression of miRNAs varied significantly between patients with AML and control individuals. The co-expression of these miRNAs was higher (P < 0.05), indicating that the presence of one miRNA led to increased expression of other miRNAs. A differential correlation was observed between miRNAs and CD markers. Additionally, miRNA 16, miRNA 21, and miRNA 221 showed significant downregulation (P < 0.05 and P < 0.01, respectively) in AML patients with COVID-19 infection compared to those without a disease. Interestingly, this study identified a higher expression level (P < 0.01) of miRNA 137 as a novel biomarker for AML patients. Moreover, the expression of miRNA 137 showed a high correlation (P < 0.05) with most of the CD markers examined in this study and FISH features data. Furthermore, a strong correlation (P < 0.01) was observed between CD markers and miRNA among AML patients with positive and negative COVID-19 infection. These data demonstrated that COVID-19 contributed to increased expression of microRNAs in AML patients. MicroRNA 137 was identified as a novel microRNA that exhibited significant differences between patients and healthy individuals, highlighting its role in AML pathogenesis.
Topics: Humans; Leukemia, Myeloid, Acute; COVID-19; Male; Female; MicroRNAs; Middle Aged; Adult; Cross-Sectional Studies; Aged; Biomarkers, Tumor; SARS-CoV-2; Antigens, CD
PubMed: 38902412
DOI: 10.1038/s41598-024-64775-1 -
Scientific Reports Jun 2024Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive...
Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.
Topics: Humans; Proto-Oncogene Proteins c-akt; Triple Negative Breast Neoplasms; Signal Transduction; Phosphatidylinositol 3-Kinases; Programmed Cell Death 1 Receptor; Cell Line, Tumor; Female; T-Lymphocytes, Cytotoxic; Interleukin-23 Subunit p19; Animals; Mice; Antibodies, Monoclonal
PubMed: 38902343
DOI: 10.1038/s41598-024-65129-7 -
Nature Communications Jun 2024The regulatory circuits dictating CD8 T cell responsiveness versus exhaustion during anti-tumor immunity are incompletely understood. Here we report that...
The regulatory circuits dictating CD8 T cell responsiveness versus exhaustion during anti-tumor immunity are incompletely understood. Here we report that tumor-infiltrating antigen-specific PD-1 TCF-1 CD8 T cells express the immunosuppressive cytokine Fgl2. Conditional deletion of Fgl2 specifically in mouse antigen-specific CD8 T cells prolongs CD8 T cell persistence, suppresses phenotypic and transcriptomic signatures of T cell exhaustion, and improves control of the tumor. In a mouse model of chronic viral infection, PD-1 CD8 T cell-derived Fgl2 also negatively regulates virus-specific T cell responses. In humans, CD8 T cell-derived Fgl2 is associated with poorer survival in patients with melanoma. Mechanistically, the dampened responsiveness of WT Fgl2-expressing CD8 T cells, when compared to Fgl2-deficient CD8 T cells, is underpinned by the cell-intrinsic interaction of Fgl2 with CD8 T cell-expressed FcγRIIB and concomitant caspase 3/7-mediated apoptosis. Our results thus illuminate a cell-autonomous regulatory axis by which PD-1 CD8 T cells both express the receptor and secrete its ligand in order to mediate suppression of anti-tumor and anti-viral immunity.
Topics: Animals; CD8-Positive T-Lymphocytes; Mice; Humans; Receptors, IgG; Programmed Cell Death 1 Receptor; Melanoma; Mice, Inbred C57BL; Mice, Knockout; Apoptosis; Female
PubMed: 38902261
DOI: 10.1038/s41467-024-49475-8 -
Nature Communications Jun 2024While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown....
While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34 progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.
Topics: Humans; Lenalidomide; Myelodysplastic Syndromes; Hematopoietic Stem Cells; Antigens, CD34; Chromosome Deletion; Chromosomes, Human, Pair 5; Single-Cell Analysis; Male; Female; Aged; Gene Regulatory Networks; Middle Aged; Hematopoiesis; Transcriptome; Aged, 80 and over; RNA-Seq; Gene Expression Profiling
PubMed: 38902243
DOI: 10.1038/s41467-024-49529-x -
Cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways by CD101.Mucosal Immunology Jun 2024T lymphocytes and myeloid cells express the immunoglobulin-like glycoprotein cluster of differentiation (CD)101, notably in the gut. Here, we investigated the...
T lymphocytes and myeloid cells express the immunoglobulin-like glycoprotein cluster of differentiation (CD)101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during dextran sulfate sodium (DSS)-induced colitis and Salmonella enterica Typhimurium infection. Similar to conventional CD101 mice, animals with a regulatory T cell-specific Cd101 deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of T helper 1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of Salmonella as revealed by studying CD101 x interferon-g mice. Moreover, CD101-expressing neutrophils were capable to restrain Salmonella infection in vitro and in vivo. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of Salmonella infection required the expression of Irg-1 and Nox2 and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of inflammatory bowel disease patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or Salmonella infection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways.
PubMed: 38901763
DOI: 10.1016/j.mucimm.2024.06.004 -
Cancer Medicine Jun 2024To investigate the sex-based heterogeneity of immune microenvironmental feature and its impact on the response to first-line PD-1 blockade plus chemotherapy in patients...
Sex-based immune microenvironmental feature heterogeneity in response to PD-1 blockade in combination with chemotherapy for patients with untreated advanced non-small-cell lung cancer.
BACKGROUND
To investigate the sex-based heterogeneity of immune microenvironmental feature and its impact on the response to first-line PD-1 blockade plus chemotherapy in patients with driver-negative advanced or metastatic non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS
A total of 439 patients with advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy or chemotherapy were identified. Differences in clinical outcomes between female and male patients were determined using Kaplan-Meier curves. Neoantigen burden and five immune microenvironmental markers expression including PD-L1, CD4, CD8, FOXP3, and CD68 were compared between two groups.
RESULTS
Of 175 eligible patients, 89 received PD-1 blockade plus chemotherapy and 86 received first-line chemotherapy. Forty five were women (25.7%) and 130 were men (74.3%). Female patients received first-line PD-1 blockade in combination with chemotherapy had dramatically better ORR (85.2% vs. 53.2%; p = 0.009), PFS (23.7 vs. 7.3 months; p = 0.013), and OS (46.2 vs. 20.0 months; p = 0.004) than males. Treatment outcomes were similar between females and males in chemotherapy group. Multivariate analyses showed that sex was the independent prognostic factor for patients received PD-1 blockade combined with chemotherapy. Although female patients had significantly lower tumor mutational and neoantigen burden than males, pretreatment tumor tissues of female patients had markedly higher CD4, CD4/FOXP3, and CD4/FOXP3/PD-L1 expression level than male patients.
CONCLUSIONS
Female patients with untreated advanced or metastatic NSCLC would derive a larger benefit from PD-1 blockade in combination with chemotherapy than males. The biological significances of heterogeneity of tumor immune microenvironmental features between them need further investigation.
Topics: Humans; Male; Carcinoma, Non-Small-Cell Lung; Female; Tumor Microenvironment; Lung Neoplasms; Middle Aged; Aged; Immune Checkpoint Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Sex Factors; Adult; Programmed Cell Death 1 Receptor; Aged, 80 and over; Biomarkers, Tumor; Retrospective Studies; Forkhead Transcription Factors
PubMed: 38899854
DOI: 10.1002/cam4.7423 -
Cancer Medicine Jun 2024Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective...
INTRODUCTION
Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center.
METHODS
All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included. Descriptive statistics were reported on patient characteristics and treatment patterns during hospital admission. Overall survival (OS) from the time of ICU discharge to death was estimated using the Kaplan-Meier method.
RESULTS
Over the study period, 5561 patients received at least one ICI administration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs. Twenty patients were treated with anti-PD-1 plus anti-CTLA-4 treatment, whereas 12 patients were treated with ICI monotherapy. The type of irAEs were de novo diabetes-related ketoacidosis (n = 8), immune-related gastrointestinal toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days (interquartile range: 2-6 days). Three patients died during ICU admission. The median OS of the patients who were discharged from the ICU was 18 months (95% confidence interval, 5.0-NA).
CONCLUSION
The incidence of irAEs leading to ICU admission in patients treated with ICI was low in this study. ICU mortality due to irAEs was low and a subset of this patient population even had long-term survival.
Topics: Humans; Immune Checkpoint Inhibitors; Male; Female; Intensive Care Units; Retrospective Studies; Middle Aged; Aged; Neoplasms; Adult; Incidence; Drug-Related Side Effects and Adverse Reactions; Aged, 80 and over; CTLA-4 Antigen
PubMed: 38899457
DOI: 10.1002/cam4.7302