Macrophage checkpoint blockade: results from initial clinical trials, binding analyses, and CD47-SIRPα structure-function.
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ABSTRACT:
SUBMITTER: Jalil AR
PROVIDER: S-EPMC7206415 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immunotherapies against some solid tumour types have recently shown unprecedented, durable cures in the clinic, and the most successful thus far involves blocking inhibitory receptor 'checkpoints' on T cells. A similar approach with macrophages is emerging by blocking the ubiquitously expressed 'marker of self' CD47 from binding the inhibitory receptor SIRPα on macrophages. Here, we first summarize available information on the safety and efficacy of CD47 blockade, which raises some safety concerns with the clearance of 'self' cells but also suggests some success against haematological (liquid) and solid cancers. Checkpoint blockade generally benefits from parallel activation of the immune cell, which can occur for macrophages in multiple ways, such as by combination with a second, tumour-opsonizing antibody and perhaps also via rigidity sensing. Cytoskeletal forces in phagocytosis and inhibitory 'self'-signalling are thus reviewed together with macrophage mechanosensing, which extends to regulating levels of SIRPα and the nuclear protein lamin A, which affects phenotype and cell trafficking. Considerations of such physical factors in cancer and the immune system can inform the design of new immunotherapies and help to refine existing therapies to improve safety and efficacy. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.
| S-EPMC6627025 | biostudies-literature
Project description:Cancer cells escape macrophage phagocytosis by expressing the CD47 integrin-associated protein that binds to the SIRPα ligand (signal regulatory protein alpha) expressed by macrophages. Immunotherapy targeting this pathway is under clinical development. We investigated the expression of CD47/SIRPα molecules in a series of 98 NSCLCs, in parallel with the infiltration of tumor stroma by CD68+ macrophages, tumor-infiltrating lymphocytes (TILs), and PD-L1/PD-1 molecules. Extensive membranous CD47 expression by cancer cells characterized 29/98 cases. SIRPα and CD68 were expressed, to a varying extent, by tumor-associated macrophages (Μφ, TAMs). A high CD68Mφ-score in inner tumor areas was linked with improved overall survival (p = 0.005); and this was independent of the stage (p = 0.02, hazard ratio 0.4). In contrast, high SIRPα expression by CD68+ TAMs (SIRPα/CD68-ratio) was linked with CD47 expression by cancer cells, low TIL-score, and poor prognosis (p = 0.02). A direct association of CD47 expression by cancer cells and the % FOXP3+ TILs (p = 0.01, r = 0.25) was also noted. TAMs play an important role in the prognosis of operable NSCLC. As SIRPα+ macrophages adversely affect prognosis, it is suggested that the CD47/SIRPα axis is a sound target for adjuvant immunotherapy policies, aiming to improve the cure rates in operable NSCLC.
| S-EPMC8997641 | biostudies-literature
Project description:Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I-deficient target cells against SIRPα+ primary NK cells, but not against SIRPα- NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα-CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell-mediated killing of allogeneic and xenogeneic tissues.
| S-EPMC7802363 | biostudies-literature
Project description:The macrophage checkpoint interaction CD47-SIRPα is an emerging target for cancer therapy, but clinical trials of monoclonal anti-CD47 show efficacy only in liquid tumors when combined with tumor-opsonizing IgG. Here, in challenging metastatic solid tumors, CD47 deletion shows no effect on tumor growth unless combined with otherwise ineffective tumor-opsonization, and we likewise show wild-type metastases are suppressed by SIRPα-blocked macrophages plus tumor-opsonization. Lung tumor nodules of syngeneic B16F10 melanoma cells with CD47 deletion show opsonization drives macrophage phagocytosis of B16F10s, consistent with growth versus phagocytosis calculus for exponential suppression of cancer. Wild-type CD47 levels on metastases in lungs of immunocompetent mice and on human metastases in livers of immunodeficient mice show that systemic injection of antibody-engineered macrophages also suppresses growth. Such in vivo functionality can be modulated by particle pre-loading of the macrophages. Thus, even though CD47-SIRPα disruption and tumor-opsonizing IgG are separately ineffective against established metastatic solid tumors, their combination in molecular and cellular therapies prolongs survival.
| S-EPMC9026896 | biostudies-literature
Project description:High-risk neuroblastoma, especially after recurrence, still has a very low survival rate. Immune checkpoint inhibitors targeting T cells have shown remarkable clinical efficacy in adult solid tumors, but their effects in pediatric cancers have been limited so far. On the other hand, targeting myeloid immune checkpoints, such as CD47-SIPRα, provide the opportunity to enhance antitumor effects of myeloid cells, including that of neutrophils, especially in the presence of cancer-opsonizing antibodies. Disialoganglioside (GD2)-expressing neuroblastoma cells targeted with anti-GD2 antibody dinutuximab are in part eradicated by neutrophils, as they recognize and bind the antibody targeted tumor cells through their Fc receptors. Therapeutic targeting of the innate immune checkpoint CD47-SIRPα has been shown to promote the potential of neutrophils as cytotoxic cells in different solid tumor indications using different cancer-targeting antibodies. Here, we demonstrate that the capacity of neutrophils to kill dinutuximab-opsonized neuroblastoma cells is also controlled by the CD47-SIRPα axis and can be further enhanced by antagonizing CD47-SIRPα interactions. In particular, CD47-SIRPa checkpoint inhibition enhanced neutrophil-mediated ADCC of dinutuximab-opsonized adrenergic neuroblastoma cells, whereas mesenchymal neuroblastoma cells may evade immune recognition by a reduction of GD2 expression. These findings provide a rational basis for targeting CD47-SIRPα interactions to potentiate dinutuximab responsiveness in neuroblastomas with adrenergic phenotype.
| S-EPMC8428220 | biostudies-literature
Project description:BACKGROUND:Accumulating preclinical data indicate that targeting the SIRPα/CD47 axis alone or in combination with existing targeted therapies or immune checkpoint inhibitors enhances tumor rejection. Although several CD47-targeting agents are currently in phase I clinical trials and demonstrate activity in combination therapy, high and frequent dosing was required and safety signals (acute anemia, thrombocytopenia) were recorded frequently as adverse events. Based on the restricted expression pattern of SIRPα we hypothesized that antibodies targeting SIRPα might avoid some of the concerns noted for CD47-targeting agents. METHODS:SIRPα-targeting antibodies were generated and characterized for binding to human SIRPα alleles and blockade of the interaction with CD47. Functional activity was established in vitro using human macrophages or neutrophils co-cultured with human Burkitt's lymphoma cell lines. The effect of SIRPα versus CD47 targeting on human T-cell activation was studied using an allogeneic mixed lymphocyte reaction and a Staphylococcus enterotoxin B-induced T-cell proliferation assay. Potential safety concerns of the selected SIRPα-targeting antibody were addressed in vitro using a hemagglutination assay and a whole blood cytokine release assay, and in vivo in a single-dose toxicity study in cynomolgus monkeys. RESULTS:The humanized monoclonal IgG2 antibody ADU-1805 binds to all known human SIRPα alleles, showing minimal binding to SIRPβ1, while cross-reacting with SIRPγ, and potently blocking the interaction of SIRPα with CD47. Reduced FcγR binding proved critical to retaining its function towards phagocyte activation. In vitro characterization demonstrated that ADU-1805 promotes macrophage phagocytosis, with similar potency to anti-CD47 antibodies, and enhances neutrophil trogocytosis. Unlike CD47-targeting agents, ADU-1805 does not interfere with T-cell activation and is not expected to require frequent and extensive dosing due to the restricted expression of SIRPα to cells of the myeloid lineage. ADU-1805 is cross-reactive to cynomolgus monkey SIRPα and upon single-dose intravenous administration in these non-human primates (NHPs) did not show any signs of anemia, thrombocytopenia or other toxicities. CONCLUSIONS:Blocking the SIRPα-CD47 interaction via SIRPα, while similarly efficacious in vitro, differentiates ADU-1805 from CD47-targeting agents with respect to safety and absence of inhibition of T-cell activation. The data presented herein support further advancement of ADU-1805 towards clinical development.
| S-EPMC6894304 | biostudies-literature
Project description:In the past decade, the field of cancer immunotherapy has rapidly advanced, establishing a crucial role for immune checkpoint blockers in the treatment of a variety of cancer types. In parallel with these remarkable clinical developments, further efforts have focused on ways of unleashing adaptive immune responses against cancer. CD47, a cell surface molecule overexpressed by several cancer types that facilitates immune escape from macrophages, dendritic cells and natural killer cells, and its ligand SIRPα, have emerged as potential therapeutic targets. A number of agents directed to CD47/SIRPα have been developed and demonstrated preclinical activity. Early phase clinical trials are investigating CD47/SIRPα directed agents with available data, suggesting safety and preliminary activity. Herein, we provide an overview of the mechanistic rationale of targeting CD47/SIRPα axis and associated clinical evidence.
| S-EPMC8699673 | biostudies-literature
Project description:In the past 25 years, a considerable number of therapeutic monoclonal antibodies (mAb) against a variety of tumor-associated antigens (TAA) have become available for the targeted treatment of hematologic and solid cancers. Such antibodies opsonize cancer cells and can trigger cytotoxic responses mediated by Fc-receptor expressing immune cells in the tumor microenvironment (TME). Although frequently ignored, neutrophils, which are abundantly present in the circulation and many cancers, have demonstrated to constitute bona fide effector cells for antibody-mediated tumor elimination in vivo. It has now also been established that neutrophils exert a unique mechanism of cytotoxicity towards antibody-opsonized tumor cells, known as trogoptosis, which involves Fc-receptor (FcR)-mediated trogocytosis of cancer cell plasma membrane leading to a lytic/necrotic type of cell death. However, neutrophils prominently express the myeloid inhibitory receptor SIRPα, which upon interaction with the 'don't eat me' signal CD47 on cancer cells, limits cytotoxicity, forming a mechanism of resistance towards anti-cancer antibody therapeutics. In fact, tumor cells often overexpress CD47, thereby even more strongly restricting neutrophil-mediated tumor killing. Blocking the CD47-SIRPα interaction may therefore potentiate neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) towards cancer cells, and various inhibitors of the CD47-SIRPα axis are now in clinical studies. Here, we review the role of neutrophils in antibody therapy in cancer and their regulation by the CD47-SIRPα innate immune checkpoint. Moreover, initial results of CD47-SIRPα blockade in clinical trials are discussed.
| S-EPMC9319280 | biostudies-literature
Project description:Cancer cells overexpress CD47 to subvert phagocytic elimination and evade immunogenic processing of cancer antigens. Moreover, CD47 overexpression inhibits the antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC) activities of therapeutic anticancer antibodies. Consequently, CD47-blocking antibodies have been developed to overcome the immunoevasive activities of cancer cell-expressed CD47. However, the wide-spread expression of CD47 on normal cells forms a massive "antigen sink" that potentially limits sufficient tumor accretion of these antibodies. Additionally, a generalized blockade of CD47-SIRPα interaction may ultimately lead to unintended cross-presentation of self-antigens potentially promoting autoimmunity. To address these issues, we constructed a bispecific antibody, designated bsAb CD47xEGFR-IgG1, that blocks cancer cell surface-expressed CD47 in an EGFR-directed manner. BsAb CD47xEGFR-IgG1 selectively induced phagocytic removal of EGFRpos/CD47pos cancer cells and endowed neutrophils with capacity to kill these cancer cells by trogoptosis; an alternate form of ADCC that disrupts the target cell membrane. Importantly, bsAb CD47xEGFR-IgG1 selectively enhanced phagocytosis and immunogenic processing of EGFRpos/CD47pos cancers cells ectopically expressing viral protein CMVpp65. In conclusion, bsAb CD47xEGFR-IgG1 may be useful to reduce on-target/off-tumor effects of CD47-blocking approaches, enhance cancer cell elimination by trogoptosis, and promote adaptive anticancer immune responses.
| S-EPMC7714490 | biostudies-literature
Project description:Rapid clearance of adoptively transferred Cd47-null (Cd47(-/-)) cells in congeneic WT mice suggests a critical self-recognition mechanism, in which CD47 is the ubiquitous marker of self, and its interaction with macrophage signal regulatory protein α (SIRPα) triggers inhibitory signaling through SIRPα cytoplasmic immunoreceptor tyrosine-based inhibition motifs and tyrosine phosphatase SHP-1/2. However, instead of displaying self-destruction phenotypes, Cd47(-/-) mice manifest no, or only mild, macrophage phagocytosis toward self-cells except under the nonobese diabetic background. Studying our recently established Sirpα-KO (Sirpα(-/-)) mice, as well as Cd47(-/-) mice, we reveal additional activation and inhibitory mechanisms besides the CD47-SIRPα axis dominantly controlling macrophage behavior. Sirpα(-/-) mice and Cd47(-/-) mice, although being normally healthy, develop severe anemia and splenomegaly under chronic colitis, peritonitis, cytokine treatments, and CFA-/LPS-induced inflammation, owing to splenic macrophages phagocytizing self-red blood cells. Ex vivo phagocytosis assays confirmed general inactivity of macrophages from Sirpα(-/-) or Cd47(-/-) mice toward healthy self-cells, whereas they aggressively attack toward bacteria, zymosan, apoptotic, and immune complex-bound cells; however, treating these macrophages with IL-17, LPS, IL-6, IL-1β, and TNFα, but not IFNγ, dramatically initiates potent phagocytosis toward self-cells, for which only the Cd47-Sirpα interaction restrains. Even for macrophages from WT mice, phagocytosis toward Cd47(-/-) cells does not occur without phagocytic activation. Mechanistic studies suggest a PKC-Syk-mediated signaling pathway, to which IL-10 conversely inhibits, is required for activating macrophage self-targeting, followed by phagocytosis independent of calreticulin Moreover, we identified spleen red pulp to be one specific tissue that provides stimuli constantly activating macrophage phagocytosis albeit lacking in Cd47(-/-) or Sirpα(-/-) mice.
| S-EPMC5027463 | biostudies-literature