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Systematic immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival.

ABSTRACT: Success of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC) has invigorated their use in neo-adjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras-mutant mouse model, we show a prevalent programmed cell death 1/ programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression. Notably, tumor progression was associated with spatiotemporal modulation of the immune microenvironment. Importantly, PD-1 inhibition controlled tumor growth, improved overall survival, and reprogrammed tumor-associated lymphoid and myeloid cells. Depletion of T lymphocyte subsets demonstrated synergistic effects of those populations on PD-1 inhibition of tumor growth. Transcriptome analyses revealed T cell subset-specific alterations corresponding to degree of response to the treatment. These results provide insights into temporal evolution of the phenotypic effects of PD-1/PD-L1 activation and inhibition, and motivate targeting this axis early in lung cancer progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE114300 | GEO | 2018/07/26

REPOSITORIES: GEO

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CXCL9/10-engineered dendritic cells promote T cell activation and enhances immune checkpoint blockade for lung cancer.

Project description:Immune checkpoint blockade (ICB), notably Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) inhibition, has revolutionized the treatment of non-small cell lung cancer (NSCLC). However, durable responses are only observed in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment can lead to deficient T-cell recruitment and ICB resistance. We evaluated in situ vaccination with CXCL9 and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a novel strategy to overcome resistance to ICB using Lkb1-null murine NSCLC model. We utilized single-cell RNA-seq to evaluate alterations of immune infiltration associated with the new therapy, which combines intratumoral CXCL9/10-DC administration and PD-1 inhibition.

2023-05-22 | GSE232730 | GEO

Transcriptomic analysis of PD-L1 positive and negative hot lung adenocarcinomas identifies a different molecular immunogenic landscape

Project description:Lung cancer is a major global health problem, as it is the leading cause of cancer- related deaths worldwide. Non-small-cell lung cancer (NSCLC), the most common form, is a heterogeneous disease with adenocarcinoma and squamous cell carcinoma being the predominant subtypes. Immune-inhibiting interaction of Programmed cell death-ligand 1 (PD-L1) with programmed cell death-protein 1 (PD-1) causes checkpoint mediated immune evasion and is, accordingly, an important therapeutic target in cancer. In NSCLC, improved understanding of PD-1/PD-L1 checkpoint blockade-responsive biology is warranted. We aimed to identify the landscape of immune cell infiltration in primary lung adeno- carcinoma (LUAD) in the context of tumor PD-L1 expression and the extent of immune infiltration (“hot” vs. “cold” phenotype). Therefore, the study comprises LUAD cases (n=138) with “hot” and “cold” tumor immune phenotype and positive and negative tumor PD-L1 expression, respectively. Tumor samples were immunohistochemically analyzed for expression of PD-L1, CD4 and CD8 and further analyzed on transcriptomic level by Nanostring nCouter Pan Cancer Immune Profiling Panel. We detected significantly differentially expressed genes associated with PD-L1 positive and “hot” versus PD-L1 negative and “cold” phenotype. The presented study illustrates novel aspects of PD-L1 regulation, with potential biological relevance, as well as relevance for immunotherapy response stratification.

2021-09-27 | GSE180347 | GEO

Gene-expression profiles of PD-L1-affected CD8+ T cells

Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.

2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress

Analysis of mouse T cell transcription profile after co-culture with BaF3 cells with or without the oncogenic point mutation JAK2 V617F

Project description:The activation of PD-1 (Programmed Death receptor-1) on T cells can cause T cell exhaustion and immune tolerance. Some tumors up-regulate the expression of the ligand of PD-1, namely PD-L1 (Programmed Death Receptor-Ligand 1), thus preventing anti-tumor immune response and promoting immune-escape. Previous studies have shown that JAK2 (Janus Kinase 2) signaling can promote PD-L1 expression in Hodgkin Lymphoma. In Myeloproliferative Neoplasms (MPN), JAK2 is frequently characterized by the the presence of the point-mutation V617F, which leads to its constitutive activation and to uncontrolled cell proliferation and survival. Accordingly, tumor cell lines expressing JAK2 V617F express higher levels of PD-L1 as compared to tumor cell lines negative for such mutations. In this experiment, we transfected BaF3 cells with a vector (plasmid for Murine Stem Cell Virus) containing the gene for JAK2 with the point-mutation V617F. As control, we used BaF3 cells transfected with the same vector, but without the gene for JAK2 V617F (empty vector). Both the cell lines (with/without JAK2 V617F) were co-cultured with primary murine T cells. When co-cultured with BaF3 cells expressing JAK2 V617F, T cells upregulated genes connected to senescence pathways, showed increased apoptosis, less cytokine production, and displayed other forms of dysfunction which can be associated with the activation of PD-1.

2018-12-01 | E-MTAB-5028 | biostudies-arrayexpress

ML29755 RNA-seq data

Project description:Programmed death-ligand 1 (PD-L1) expression has been associated with response to PD-1/PD-L1 inhibition, but responses are also seen in patients with PD-L1 negative tumors when assessed immunohistochemically (IHC) with various antibodies. To help elucidate these findings, we performed a positron emission tomography (PET) imaging study in human with the anti-PD-L1 antibody atezolizumab labeled with Zirconium-89 (89Zr) prior to treatment with atezolizumab to assess normal tissue distribution and evaluate tumor tracer uptake. Additionally, to help explain why some patients respond to checkpoint inhibitors despite low or absent PD-L1 expression, we compared PD-L1 expression and immune phenotypes based on both CD8 IHC and RNA sequencing of post-tracer biopsies to tumor tracer uptake (SUVmax).

2018-06-12 | GSE115594 | GEO

Gene-expression profiles of ascites-cytology-positive ovarian cancer

Project description:Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Positive cytology in ascites was a significant poor prognostic factor in ovarian cancer. Microarray profiles of cytology-positive cases showed significant correlations with Gene Ontology terms related to immune system process. Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and positive cytology. PD-L1 expression on mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and upon co-culturing with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in human ovarian cancer tissue from ascites-cytology-positive or -negative patients.

2012-07-09 | E-GEOD-39204 | biostudies-arrayexpress

Application of peptide barcoding to obtain high-affinity anti-PD-1 nanobodies

Project description:Cancer treatment has been revolutionized by immune checkpoint inhibitors, which regulate immune cell function by blocking the interactions between immune checkpoint molecules and their ligands. The interaction between programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) is a target for immune checkpoint inhibitors. Nanobodies, which are recombinant variable domains of heavy-chain-only antibodies, can replace existing immune checkpoint inhibitors, such as anti-PD-1 or anti-PD-L1 conventional antibodies. However, the screening process for high-affinity nanobodies is laborious and time-consuming. Here, we identified high-affinity anti-PD-1 nanobodies using peptide barcoding, which enabled reliable and efficient screening by distinguishing each nanobody with a peptide barcode that was genetically appended to each nanobody. We prepared a peptide-barcoded nanobody (PBNb) library with thousands of variants. Three high-affinity PBNbs were identified from the PBNb library by quantifying the peptide barcodes derived from high-affinity PBNbs. Furthermore, these three PBNbs neutralized the interaction between PD-1 and PD-L1. Our results demonstrate the utility of peptide barcoding and the resulting nanobodies can be used as experimental tools and antitumor agents. Peptide barcoding can be used to screen for molecules other than nanobodies. Our methods, such as the design of peptide barcodes, the design of peptide-barcoded molecules, preparation of peptide-barcoded molecule library, and quantification of peptide barcodes, are helpful in screening for peptide-barcoded molecules.

2024-03-21 | PXD041000 | JPOST Repository

Activation and acetylation of tumor-intrinsic PD-L1 via HBXIP accelerates breast cancer growth

Project description:Programmed death ligand-1 (PD-L1) is a well-known transmembrane protein, which antibodies present effective clinical therapy in multiple human cancers. However, the function of tumor cell-intrinsic PD-L1 and its related mechanism in breast cancer remains incompletely studied. Programmed death ligand 1 (PD-L1) on the membrane of tumor cells strengthens tumor immune escape. Tumor cell-intrinsic PD-L1 is also involved in tumorigenesis and development, but the mechanism in regulating PD-L1 expression remains incompletely studied. Here, we report a novel mechanism for PD-L1 that can be induced by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, promoting breast cancer growth. Overexpression of PD-L1 increases breast cancer proliferation in vitro and in vivo. Transcriptomic analysis also reveals that PD-L1 plays a critical role in cancer development. Furthermore, we find that the expression of PD-L1 is positively associated with HBXIP in breast cancer clinical tissues as well as in cell lines, PD-L1 and HBXIP expression have higher levels in tumor. Mechanistically, HBXIP predominantly stimulates the promoter activity of PD-L1 through coactivating transcription factor ETS2. Especially, HBXIP induced PD-L1 acetylation with the acetyltransferase p300 at lysine 270 (K270), enhancing PD-L1 protein stability. Functionally, depletion of HBXIP markedly attenuates PD-L1-induced breast tumor growth in vitro and in vivo. Moreover, aspirin decreased breast cancer growth via targeting PD-L1 and HBXIP. Taken together, our results extend a new mechanism of PD-L1 functions, expound non-immune effects of PD-L1 and imply broader uses for PD-L1 as a target in breast cancer therapy.

2022-02-02 | GSE158696 | GEO

Human RKO cells LC-MSMS (gel-based proteomics)

Project description:Tumor cells evade T cell-mediated immunosurveillance via the interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells. Strategies disrupting PD-1/PD-L1 have shown clinical benefits in various cancers. However, the limited response rate prompts us to investigate the molecular regulation of PD-L1. Here we identify trafficking protein particle complex subunit 4 (TRAPPC4), a major player in vesicular trafficking, as a crucial PD-L1 regulator. TRAPPC4 interacts with PD-L1 in recycling endosomes, promoting RAB11-mediated recycling of PD-L1, and acting as a scaffold between PD-L1 and RAB11, thus replenishing its distribution on the tumor cell surface.

2021-08-15 | PXD027826 | Pride

Gene-expression profiles of PD-L1-affected CD8+ T cells

2012-07-10 | GSE39205 | GEO

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