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Detection of Cell-Cell Interactions via Photocatalytic Cell Tagging

ABSTRACT: The growing appreciation of immune cell-cell interactions within disease environments has led to significant efforts to develop highly effective protein-, and cell-based immunotherapies.  However, characterizing these complex cell-cell interactions in high resolution remains challenging.  Thus, technologies that leverage therapeutic-based modalities for profiling intercellular environments can provide unique advantages towards understanding these cellular interactions at molecular-level detail.  To address this, we introduce photocatalytic cell tagging (PhoTag), a platform for profiling cell-cell interactions that utilizes a single domain antibody (VHH) conjugated to a photoactivatable flavin-based cofactor.  Upon irradiation with visible light, the tethered flavin photocatalyst generates phenoxy radical tags for targeted labeling within cell-cell contact environments.  Using anti-PD-1 or anti-PD-L1 VHH flavin conjugates, we demonstrate that PhoTag achieves highly selective synaptic labeling in antigen presenting cell-T cell co-culture systems. By combining the high resolution transcellular biotinylation capability of PhoTag with multi-omics single cell sequencing, we interrogated transient interactions between Peripheral blood mononuclear cell (PBMC) populations and Raji PD-L1 B cells and discovered that specific T cell subtypes can transiently interact more efficiently than others.   We envision that the spatio-temporal and modular nature of PhoTag will enable its broad utilization for detailed profiling of intercellular interactions across different biological systems. 

ORGANISM(S): Homo sapiens

PROVIDER: GSE206140 | GEO | 2022/06/18

REPOSITORIES: GEO

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Detection of Cell-Cell Interactions via Photocatalytic Cell Tagging

Project description:The growing appreciation of immune cell-cell interactions within disease environments has led to significant efforts to develop highly effective protein- and cell-based immunotherapies. However, characterizing these complex cell-cell interfaces in high resolution remains challenging. Thus, technologies that can leverage therapeutic-based modalities to profile intercellular environments offer the opportunity to study cell-cell interactions with molecular-level insight. To address this, we introduce Photocatalytic Cell Tagging (PhoTag), a platform for profiling cell-cell interactions utilizing a single domain antibody (VHH) conjugated to a photoactivatable flavin-based cofactor. Upon irradiation with visible light, the tethered flavin photocatalyst generates phenoxy radical tags for targeted labeling within cell-cell contact regions. Using anti-PD-1 or anti-PD-L1 VHH flavin conjugates, we demonstrate that PhoTag achieves highly selective synaptic labeling in antigen presenting cell-T cell co-culture systems. By combining the high resolution transcellular biotinylation capability of PhoTag with multi-omics single cell sequencing, we interrogated transient interactions between peripheral blood mononuclear cell (PBMC) populations and Raji PD-L1 B cells and discovered that specific T cell subtypes can transiently interact more efficiently than others. We envision that the spatiotemporal and modular nature of PhoTag will enable its broad utilization for detailed profiling of intercellular interactions across different biological systems.

2022-06-03 | PXD032203 | Pride

Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance

Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.

2022-03-31 | MSV000089180 | MassIVE

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

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

EIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer

Project description:Cancer cells express high levels of PD-L1, a ligand of the PD-1 receptor on T cells, allowing tumors to suppress T cell activity 1-3. Clinical trials utilizing monoclonal antibodies that disrupt the PD-1/PD-L1 immune checkpoint have yielded remarkable results, with PD-1 immunotherapy approved as a first-line therapy for human lung cancer patients 4-6. Despite significant progress in targeting this pathway, the mechanisms through which PD-L1 is upregulated in non-small cell lung cancer (NSCLC) and other tumor types remain incompletely understood. Here we used CRISPR-based screening to identify regulators of PDL1 in human lung cancer cells, revealing potent induction of PD-L1 levels upon disruption of the heme biosynthesis pathway. Impairment of heme production activates the integrated stress response (ISR), allowing bypass of inhibitory upstream open reading frames in the PD-L1 5¢ UTR, resulting in enhanced PD-L1 translation and suppression of anti-tumor immunity. We further demonstrated that ISR-dependent translation of PD-L1 requires the translation initiation factor EIF5B. EIF5B overexpression, which is frequent in human lung cancers and is associated with poor prognosis, is sufficient to induce PD-L1. These findings uncover a new mechanism of immune checkpoint activation and suggest novel targets for therapeutic intervention.

2020-02-01 | GSE129968 | GEO

PD-L1 – PD-1 interactions limit effector Treg cell populations at homeostasis and during infection

Project description:PD-L1 – PD-1 interactions limit effector Treg cell populations at homeostasis and during infection

| PRJNA773432 | ENA

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

Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma [RNA-Seq]

Project description:PD-L1 is a ligand for the inhibitory PD1 receptor on T cells and its expression in some cancers inhibits anti-cancer immune response. In melanoma, PD-L1 expression is induced in response to immune stimuli but in a proportion of melanomas it is constitutively expressed. Factors that drive constitutive expression of PD-L1 are unknown. Here we performed RNA-Seq analysis of six cell lines that constitutively express PD-L1 (PD-L1 positive, referred to as PD-L1CON) and six cell lines that only express PD-L1 after treatment with IFN- (PD-L1 negative, referred to as PD-L1IND)

2018-05-24 | GSE107620 | GEO

Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma [RRBS]

Project description:PD-L1 is a ligand for the inhibitory PD1 receptor on T cells and its expression in some cancers inhibits anti-cancer immune response. In melanoma, PD-L1 expression is induced in response to immune stimuli but in a proportion of melanomas it is constitutively expressed. Factors that drive constitutive expression of PD-L1 are unknown. Here we performed genome-scale methylation analysis of six cell lines that constitutively express PD-L1 (PD-L1 positive, referred to as PD-L1CON) and six cell lines that only express PD-L1 after treatment with IFN- (PD-L1 negative, referred to as PD-L1IND)

2018-05-24 | GSE107621 | GEO

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

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