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PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model

ABSTRACT: Alzheimer’s disease (AD) is a heterogeneous disorder with multiple etiologies. Harnessing the immune system by blocking the programmed cell death receptor (PD)-1 pathway in an amyloid beta mouse model was shown to evoke a sequence of immune responses that lead to disease modification. Here, blocking PD-L1, a PD-1 ligand, was found to have similar efficacy to that of PD-1 blocking in disease modification, in both animal models of AD and of tauopathy. Targeting PD-L1 in a tau-driven disease model resulted in increased immunomodulatory monocyte-derived macrophages within the brain parenchyma. Single cell RNA-seq revealed that the homing macrophages expressed unique scavenger molecules including macrophage scavenger receptor 1 (MSR1), which was shown here to be required for the effect of PD-L1 blockade in disease modification. Overall, our results demonstrate that immune checkpoint blockade targeting the PD-1/PD-L1 pathway leads to modification of common factors that go awry in AD and dementia, and thus can potentially provide an immunotherapy to help combat these diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE130008 | GEO | 2019/04/18

REPOSITORIES: GEO

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Blood-borne macrophages contribute to Alzheimer's disease modification through a TREM2-independent pathway

Project description:Microglia and monocyte-derived macrophages (MDM) are key players in coping with Alzheimer's disease (AD). In amyloidosis mouse models, activation of microglia was found to be TREM2-dependent. Here, using Trem2-/-5xFAD mice, we assessed whether MDM act via a TREM2-dependent pathway. We adopted a treatment protocol targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, previously shown to modify AD via MDM involvement. Blocking PD-L1 in Trem2-/-5xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta (Aβ)1-42 with no effect on amyloid plaque burden. Single-cell RNA sequencing revealed that MDM, derived from both Trem2-/- and Trem2+/+5xFAD mouse brains, express a unique set of genes encoding scavenger receptors (e.g. Mrc1, Msr1). Blocking monocytes trafficking using anti-CCR2 antibody completely abrogated the cognitive improvement induced by anti-PD-L1 in Trem2-/-5xFAD mice, and similarly but to lower extent in Trem2+/+5xFAD mice. These results highlight a TREM2-independent disease-modifying activity of MDM in amyloidosis mouse model.

2021-10-24 | GSE176085 | GEO

Expression data in PD-L1 positive and PD-L1 negative human melanoma samples

Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.

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Expression data from CD8 T cells from LCMV-Clone13 infected mice after two weeks of control or anti-PD-L1 treatment

Project description:Blocking PD-1 can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. One potential advantage of this immunotherapy is durable protection if immune memory can be established. It is unclear, however, whether blocking PD-1 can reprogram TEX into effector (TEFF) or durable memory T cells (TMEM). Here, we found reinvigoration of TEX by PD-L1 blockade caused re-acquisition of some features of TEFF, but minimal memory development. We used microarray analysis to profile exhausted cells from anti-PD-L1 mice after two weeks of treatment to study if PD-L1 blockade caused re-acquistion of some feature of effector or memory cells.

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High Response Rate to Anti PD-1 Therapy in Desmoplastic Melanoma

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| phs001469 | dbGaP

Peptide ‘Nano-Spiderwebs’ for Cancer Immunotherapy: New Receptor-Engineered Supramolecular Antagonists to PD-L1

Project description:Immunol checkpoint blockade therapy targeting programmed-death 1 (PD-1) and its ligand PD-L1 can effectively prevent tumor immune escaping, and has been recognized with remarkable clinical benefits on cancer. Currently, antibody drugs take effect by blocking the target on the cell membrane. However, antibody drugs still face challenges in the aspect of deep penetration, multivalent recognition and chemical synthesis. Rationally designed targeting peptides is the befitting units for construction of the ‘nano antibody’. We first report herein a new peptide-AIE (aggregation-induced emission) hybrid supramolecular TPDP, which can specifically bind PD-L1 in vivo and in vitro with nanomolar affinity. It can be triggered by PD-L1 into ordered-aggregation ‘nano-spiderwebs’ and compactly cocoon the lesion surface and block PD-1/PD-L1 interaction on both membrane and cytoplasm in a dynamic manner, showing competitive effect over antibodies. It showed excellent in vivo tumor therapy effect in patient derived xenograft mice (PDX). What’s more, PD-L1 targeted antibody drugs take effect by blocking PD-L1 on the cell membrane, but intracellular PD-L1 are hard to be affect and like to be relocated on the membrane, which decreases the therapeutic benefits. In this study, the nano-spiderwebs could penetrate deeply into the cytoplasm and down-regulate the endogenous PD-L1 expression of the host, which could reduce the feedback of intracellular storage of PD-L1. We envision that this receptor-induced peptide ‘nano-spiderwebs’ will open an avenue for both blockade and inhibitor against PD-L1 and provide alternatives for targeting diagnostics and therapeutics towards this immune checkpoint.

2020-08-15 | PXD020918 |

Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment (bulk)

Project description:A hallmark of PD-1/L1 blockade is long-term, sustained remission of metastatic disease. How the immune system coordinates the destruction of macro- and micro-metastases following checkpoint blockade, however, remains unclear. Here, we show that tumor-expressed PD-L1 (tPD-L1) enhanced metastasis in a mechanism distinct from and independent of its role in primary tumor growth. This difference in metastatic growth was mediated by cytotoxic T lymphocytes (CTLs), however, tPD-L1 did not promote effector CTL exhaustion or suppress lytic activity in vivo. Instead, single cell RNA sequencing revealed that tPD-L1 engaged macrophage-expressed PD-1 to antagonize type I interferon production and signaling, creating an immunologically ‘cold’ microenvironment. Loss of tPD-L1 eliminated metastases by driving interferon-mediated sensitization of tumor cells to CTL lysis and CTL recruitment.

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Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment (single cells)

2023-02-06 | GSE150742 | GEO

Expression data in PD-L1 positive and PD-L1 negative human melanoma samples

2015-05-01 | GSE65041 | GEO

Gene signature profiles in lung tisses of wild type mice or PD-1 or PD-L1 deficient mice infected with Mycobacterium avium

Project description:Rationale: T cell activation is a key antimicrobial component against mycobacterial disease. Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) pathway could affect the antimicrobial immune responses by suppressing T cell activity. Several recent studies demonstrated that blocking of PD-1/PD-L1 pathway exacerbated Mycobacterium tuberculosis infection. However, the influence of blocking this pathway in pulmonary Mycobacterium avium-intracellulare complex (MAC) infection was not fully understood. Objective: We aimed to determine the influence of genetic depletion of PD-1/PD-L1 pathway on the disease activity of MAC infection. Methods: Wild-type, PD-1-deficient mice and PD-L1-deficient mice were intranasally infected with Mycobacterium avium bacteria. Measurements and Main Results: The depletion of PD-1 or PD-L1 did not affect mortality and bacterial burden in mice infected with MAC. However, remarkable infiltration of CD8 T lymphocytes was observed in the lungs of PD-1 and PD-L1 deficient mice compared to wild-type mice. Comprehensive transcriptome analysis showed that levels of gene expressions related to Th1 immunity did not differ according to the genotypes. However, genes related to the activity of CD8 T cells and related chemokine activity were up-regulated in the infected lungs of PD-1 and PD-L1 deficient mice. Conclusions: Depletion of PD-1/PD-L1 pathway did not affect the activation of Th1 immunity in response to MAC infection, which may explain why MAC infection was controlled in these mice. In addition, CD8-positive T cell pulmonary inflammation in knockout mice might have some clinical implication in the treatment of cancer patients with immune checkpoint inhibitors when the patients are infected with MAC.

2021-09-15 | GSE169202 | GEO

Batf3-dendritic cells and 4-1BB/4-1BB ligand axis are required at the effector phase within the tumor microenvironment for PD-1/PD-L1 blockade efficacy

Project description:The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of PD-1/PD-L1 blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL was a major positive costimulatory signal provided by these DCs within the TME, that translated to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlated with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME was associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy, and indicate a major role for the 4-1BB/4-1BBL axis during this process.

2024-05-13 | GSE238145 | GEO

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