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Frontiers in Immunology 2024The ubiquitously expressed transmembrane glycoprotein CD47 participates in various important physiological cell functions, including phagocytosis, apoptosis,... (Review)
Review
The ubiquitously expressed transmembrane glycoprotein CD47 participates in various important physiological cell functions, including phagocytosis, apoptosis, proliferation, adhesion, and migration, through interactions with its ligands, including the inhibitory receptor signal regulatory protein α (SIRPα), secreted glycoprotein thrombospondin-1 (TSP-1), and integrins. Elevated expression of CD47 is observed in a wide range of cancer cells as a mechanism for evading the immune system, blocking the interaction between the CD47 and SIRPα is the most advanced and promising therapeutic approach currently investigated in multiple clinical trials. The widely held view that a single type of CD47 protein acts through membrane interactions has been challenged by the discovery of a large cohort of CD47 proteins with cell-, tissue-, and temporal-specific expression and functional profiles. These profiles have been derived from a single gene through alternative splicing and post-translational modifications, such as glycosylation, pyroglutamate modification, glycosaminoglycan modification, and proteolytic cleavage and, to some extent, via specific CD47 clustering in aging and tumor cells and the regulation of its subcellular localization by a pre-translational modification, alternative cleavage and polyadenylation (APA). This review explores the origins and molecular properties of CD47 proteoforms and their roles under physiological and pathological conditions, mentioning the new methods to improve the response to the therapeutic inhibition of CD47-SIRPα immune checkpoints, contributing to the understanding of CD47 proteoform diversity and identification of novel clinical targets and immune-related therapeutic candidates.
Topics: Humans; CD47 Antigen; Receptors, Immunologic; Antigens, Differentiation; Phagocytosis; Integrins
PubMed: 38426113
DOI: 10.3389/fimmu.2024.1329562 -
Cancer Research Nov 2023Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy; however, their application is limited by the occurrence of immune-related adverse events. The gut...
UNLABELLED
Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy; however, their application is limited by the occurrence of immune-related adverse events. The gut microbiota plays important roles in the response to and toxicity of immunotherapy and Faecalibacterium prausnitzii (F. prausnitzii) has been shown to possess immunomodulatory potential. Here, we found that patients receiving ICIs who developed colitis had a lower abundance of F. prausnitzii. In vivo, immunocompetent mice administered with dextran sodium sulfate and immunodeficient NSG mice with human peripheral blood mononuclear cell transfer were treated with ICIs to study ICI-induced colitis. Dual CTLA4 and PD-1 blockade exacerbated autoimmune colitis, activated an inflammatory response, and promoted myeloid cell infiltration, with higher percentages of macrophages, dendritic cells, monocytes, and neutrophils. F. prausnitzii administration mitigated the exacerbated colitis induced by ICIs. Concomitantly, F. prausnitzii enhanced the antitumor immunity elicited by ICIs in tumor-bearing mice while abrogating colitis. In addition, administration of F. prausnitzii increased gut microbial alpha diversity and modulated the microbial composition, increasing a subset of gut probiotics and decreasing potential gut pathogens. F. prausnitzii abundance was reduced in mice that developed ICI-associated colitis. Together, this study shows that F. prausnitzii administration ameliorates ICI-induced colitis, reshapes the gut microbial composition, and enhances the antitumor activity of immunotherapy.
SIGNIFICANCE
F. prausnitzii alleviates colitis while enhancing the tumor-suppressive effects of immune checkpoint blockade, indicating that supplementation with F. prausnitzii could be a treatment strategy to mitigate immunotherapy toxicity in patients with cancer.
Topics: Humans; Mice; Animals; Faecalibacterium prausnitzii; Programmed Cell Death 1 Receptor; Leukocytes, Mononuclear; CTLA-4 Antigen; Colitis; Neoplasms
PubMed: 37602831
DOI: 10.1158/0008-5472.CAN-23-0605 -
Gastroenterology Jun 2024Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS...
Tertiary Lymphoid Structure-Associated B Cells Enhance CXCL13CD103CD8 Tissue-Resident Memory T-Cell Response to Programmed Cell Death Protein 1 Blockade in Cancer Immunotherapy.
BACKGROUND & AIMS
Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS enhances antitumor immunity is not well understood. The present study aimed to investigate the underlying cross talk circuits between B cells and tissue-resident memory T (Trm) cells within the TLS and to understand their role in the context of immunotherapy.
METHODS
Immunostaining and H&E staining of TLS and chemokine (C-X-C motif) ligand 13 (CXCL13) cluster of differentiation (CD)103CD8 Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13CD103CD8 Trm cells was determined in vitro and in vivo. The effect of CXCL13CD103CD8 Trm cells in suppressing tumor growth was evaluated through anti-programmed cell death protein (PD)-1 therapy.
RESULTS
The presence of TLS and CXCL13CD103CD8 Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in patients with GC. Additionally, our research identified that activated B cells enhanced CXCL13 and granzyme B secretion by CD103CD8 Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103CD8 Trm cells through the lymphotoxin-α/tumor necrosis factor receptor 2 (TNFR2) axis, and the mechanistic target of rapamycin signaling pathway played a critical role in CD103CD8 Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13CD103CD8 Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2-dependent manner.
CONCLUSIONS
This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13CD103CD8 Trm cells in antitumor immunity, providing valuable insights into the potential use of the lymphotoxin-α/TNFR2 axis within CXCL13CD103CD8 Trm cells for advancing immunotherapy strategies in GC.
Topics: Chemokine CXCL13; Humans; Tertiary Lymphoid Structures; Programmed Cell Death 1 Receptor; CD8-Positive T-Lymphocytes; B-Lymphocytes; Stomach Neoplasms; Antigens, CD; Integrin alpha Chains; Memory T Cells; Animals; Immune Checkpoint Inhibitors; Granzymes; Lymphocytes, Tumor-Infiltrating; Immunologic Memory; Signal Transduction; Tumor Microenvironment; TOR Serine-Threonine Kinases; Mice; Immunotherapy; Cell Line, Tumor
PubMed: 38445519
DOI: 10.1053/j.gastro.2023.10.022 -
Annals of the Rheumatic Diseases Mar 2024
Topics: Humans; Scleroderma, Systemic; Antigens, CD19; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 38135464
DOI: 10.1136/ard-2023-225174 -
Nature Jun 2024Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system. Here...
Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47 are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.
Topics: Animals; Female; Humans; Male; Mice; Antigens, Differentiation; CD47 Antigen; Cell Line, Tumor; Immunotherapy, Adoptive; Macrophages; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Receptors, Immunologic; T-Lymphocytes; Tumor Microenvironment; Antibodies; Macrophage Activation
PubMed: 38750365
DOI: 10.1038/s41586-024-07443-8 -
European Journal of Immunology Nov 2023Signal regulatory protein alpha (SIRPα) is a crucial inhibitory regulator expressed on the surface of myeloid cells, including macrophages, dendritic cells, monocytes,... (Review)
Review
Signal regulatory protein alpha (SIRPα) is a crucial inhibitory regulator expressed on the surface of myeloid cells, including macrophages, dendritic cells, monocytes, neutrophils, and microglia. SIRPα plays an indispensable role in innate immune and adoptive immune responses in cancer immunology, tissue homeostasis, and other physiological or phycological conditions. This review provides an overview of the research history, ligands, signal transduction pathways, and functional mechanisms associated with SIRPα. Additionally, we summarize the therapeutic implications of targeting SIRPα as a promising novel strategy in immuno-oncology.
Topics: Humans; Phagocytosis; Immunity, Innate; Macrophages; Neoplasms; Myeloid Cells; Antigens, Differentiation
PubMed: 37672390
DOI: 10.1002/eji.202350375 -
Cells Feb 2024Interactions among leukocytes and leukocytes with immune-associated auxiliary cells represent an essential feature of the immune response that requires the involvement... (Review)
Review
Interactions among leukocytes and leukocytes with immune-associated auxiliary cells represent an essential feature of the immune response that requires the involvement of cell adhesion molecules (CAMs). In the immune system, CAMs include a wide range of members pertaining to different structural and functional families involved in cell development, activation, differentiation and migration. Among them, β integrins (LFA-1, Mac-1, p150,95 and αβ) are predominantly involved in homotypic and heterotypic leukocyte adhesion. β2 integrins bind to intercellular (I)CAMs, actin cytoskeleton-linked receptors belonging to immunoglobulin superfamily (IgSF)-CAMs expressed by leukocytes and vascular endothelial cells, enabling leukocyte activation and transendothelial migration. β2 integrins have long been viewed as the most important ICAMs partners, propagating intracellular signalling from β2 integrin-ICAM adhesion receptor interaction. In this review, we present previous evidence from pioneering studies and more recent findings supporting an important role for ICAMs in signal transduction. We also discuss the contribution of immune ICAMs (ICAM-1, -2, and -3) to reciprocal cell signalling and function in processes in which β2 integrins supposedly take the lead, paying particular attention to T cell activation, differentiation and migration.
Topics: Humans; Endothelial Cells; Cell Adhesion Molecules; Lymphocyte Function-Associated Antigen-1; Macrophage-1 Antigen; CD18 Antigens; Communication
PubMed: 38391953
DOI: 10.3390/cells13040339 -
Cancer Immunology Research Dec 2023T cells recognize several types of antigens in tumors, including aberrantly expressed, nonmutated proteins, which are therefore shared with normal tissue and referred to...
T cells recognize several types of antigens in tumors, including aberrantly expressed, nonmutated proteins, which are therefore shared with normal tissue and referred to as self/shared-antigens (SSA), and mutated proteins or oncogenic viral proteins, which are referred to as tumor-specific antigens (TSA). Immunotherapies such as immune checkpoint blockade (ICB) can activate T-cell responses against TSA, leading to tumor control, and also against SSA, causing immune-related adverse events (irAE). To improve anti-TSA immunity while limiting anti-SSA autoreactivity, we need to understand how tumor-specific CD8+ T cells (TST) and SSA-specific CD8+ T (SST) cells differentiate in response to cognate antigens during tumorigenesis. Therefore, we developed a genetic cancer mouse model in which we can track TST and SST differentiation longitudinally as liver cancers develop. We found that both TST and SST lost effector function over time, but while TST persisted long term and had a dysfunctional/exhausted phenotype (including expression of PD1, CD39, and TOX), SST exited cell cycle prematurely and disappeared from liver lesions. However, SST persisted in spleens in a dysfunctional TCF1+PD-1- state: unable to produce effector cytokines or proliferate in response to ICB targeting PD-1 or PD-L1. Thus, our studies identify a dysfunctional T-cell state occupied by T cells reactive to SSA: a TCF1+PD-1- state lacking in effector function, demonstrating that the type/specificity of tumor antigen may determine tumor-reactive T-cell differentiation.
Topics: Animals; Mice; Programmed Cell Death 1 Receptor; CD8-Positive T-Lymphocytes; Liver Neoplasms; Cytokines; Lymphocyte Activation; Antigens
PubMed: 37844197
DOI: 10.1158/2326-6066.CIR-22-0939 -
Biochemical Pharmacology Nov 2023The CD40 receptor and its ligand CD154 are widely expressed in various immune-competent cells. Interaction of CD154 with CD40 is essential for B-cell growth,... (Review)
Review
The CD40 receptor and its ligand CD154 are widely expressed in various immune-competent cells. Interaction of CD154 with CD40 is essential for B-cell growth, differentiation, and immunoglobulin class switching. Many other immune-competent cells involved in innate and adaptive immunity communicate through this co-stimulatory ligand-receptor dyad. CD40-CD154 interaction is involved in the pathogenesis of numerous inflammatory and autoimmune diseases. While CD40 and CD154 are membrane-bound proteins, their soluble counterparts are generated by proteolytic cleavage or alternative splicing. This review summarises current knowledge about the impact of single nucleotide polymorphisms in the human CD40 gene and compensatory changes in the plasma level of the soluble CD40 receptor (sCD40) isoform in related pro-inflammatory diseases. It discusses regulation patterns of the disintegrin metalloprotease ADAM17 function leading to ectodomain shedding of transmembrane proteins, such as pro-inflammatory adhesion molecules or CD40. The role of sCD40 as a potential biomarker for chronic inflammatory diseases will also be discussed.
Topics: Humans; Ligands; CD40 Antigens; CD40 Ligand; Chronic Disease; Membrane Proteins
PubMed: 37863325
DOI: 10.1016/j.bcp.2023.115858 -
Nature Immunology Nov 2023
Topics: Programmed Cell Death 1 Receptor
PubMed: 37845493
DOI: 10.1038/s41590-023-01677-w