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PD-L1 Engagement on T cells Promotes Self-tolerance and Suppression of Neighboring Macrophages and Effector T cells in Cancer

ABSTRACT: PD-1 ligation delimits immunogenic responses in T cells. However, the consequences of PD-L1 ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor-antigen, microbial signals, and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (i) Binding of PD-L1 induced STAT3-dependent back-signaling in CD4+ T cells preventing activation, reducing Th1-polarization, and directing Th17-differentiation. PD-L1 signaling also induced an anergic Tbet-IFNg- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling. (ii) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis even in the absence of endogenous PD-L1. (iii) PD-L1+ T cells engaged PD-1+ macrophages inducing an alternative M2-like program, which had crippling effects on adaptive anti-tumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE145905 | GEO | 2020/05/19

REPOSITORIES: GEO

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Combined PD-L1/TGFb blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8 T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.

2023-06-16 | MSV000092193 | MassIVE

Epigenetic targeting of immunocheckpoint PD-L1 by BET bromodomain inhibition

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2016-10-17 | GSE81698 | GEO

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2020-06-07 | GSE146557 | GEO

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2020-06-07 | GSE134510 | GEO

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

RNA-Seq analysis to compare myeloid cells from PD-L1-LysMCre mice with littermate Wild-type controls

Project description:Programmed death-ligand 1 (PD-L1) is predominantly expressed in the antigen-presenting cells (APCs) that are originated and abundant in bone marrow. The roles of PD-L1 in bone cell differentiation and cancer bone metastasis remain unclear. Here we show that PD-L1 antibody or PD-L1 conditional knockout in the hematopoietic or myeloid lineage suppresses osteoclast differentiation in vitro and in vivo. Bone metastases of breast cancer and melanoma are diminished by PD-L1 antibody or PD-L1 deletion in the myeloid lineage. Transcriptional profiling of bone marrow cells reveals that PD-L1 deletion in the myeloid cells up-regulates immune stimulatory genes, leading to increased macrophage M1 polarization, decreased M2 polarization, enhanced IFN? signaling, and elevated T cell recruitment and activation. All these alterations result in heightened anti-tumor immunity in the cancer microenvironment. Our findings support PD-L1 antibody as a potent therapy for bone metastasis of breast cancer and melanoma by simultaneously suppressing osteoclast and enhancing immunity.

2022-03-07 | GSE190715 | GEO

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

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

β3-adrenergic receptor on tumor-infiltrating lymphocytes sustains IFN-γ-dependent PD-L1 expression and impairs anti-tumor immunity in a murine model of neuroblastoma

Project description:A distinctive feature of neuroblastoma (NB) tumors is their ability to secrete neuroendocrine mediators such as catecholamines, which through β-adrenergic receptors ligation may influence different signaling pathways in the tumor microenvironment (TME). Here, we aimed to investigate whether the β3-AR modulation affected the host immune system response to NB tumor. In a murine syngeneic NB model, pharmacological β3-AR antagonism lead to an immune response reactivation and reduced tumor growth through the involvement of PD-1/PD-L1 signaling axis. Indeed, β3-AR blockade on tumor infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-γ and reduced PD-L1 expression on NB tumor cells, preventing the establishment of an immune suppressive TME. Furthermore, genomic analysis on NB patients showed that high ADRB3 gene expression correlates with poor clinical outcome. Overall, these findings indicate that β3-AR is able to sustain an immune suppressive TME in NB via PD-1/PD-L1 crosstalk, and suggest that targeting β-adrenergic signaling in NB could represent a new strategy to overcome immune escape gateway.

2023-07-31 | GSE209634 | GEO

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