Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients

AbstractOvercoming tumor-mediated immunosuppression and enhancing cytotoxic T-cell activity within the tumor microenvironment are two central goals of immuno-oncology (IO) drug discovery initiatives. However, exploratory assays involving immune components are often plagued by low-throughput and poor clinical relevance. Here we present an innovative ultra-high-content assay platform for interrogating T-cell-mediated killing of 3D multicellular tumor spheroids. Employing this assay platform in a chemical genomics screen of 1800 annotated compounds enabled identification of small molecule perturbagens capable of enhancing cytotoxic CD8+ T-cell activity in an antigen-dependent manner. Specifically, cyclin-dependent kinase (CDK) and bromodomain (BRD) protein inhibitors were shown to significantly augment anti-tumor T-cell function by increasing cytolytic granule and type II interferon secretion in T-cells in addition to upregulating major histocompatibility complex (MHC) expression and antigen presentation in tumor cells. The described biotechnology screening platform yields multi-parametric, clinically-relevant data and can be employed kinetically for the discovery of first-in-class IO therapeutic agents.

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Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

Cancer Microenvironment ◽

10.1007/s12307-012-0096-9 ◽

2012 ◽

Vol 6 (1) ◽

pp. 57-68 ◽

Cited By ~ 8

Author(s):

Jessica M. S. Jutzy ◽

Salma Khan ◽

Malyn May Asuncion-Valenzuela ◽

Terry-Ann M. Milford ◽

Kimberly J. Payne ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

Cell Function ◽

T Cell Response ◽

Cytotoxic T Cell ◽

T Cell Function

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Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155416672418 ◽

2016 ◽

Vol 64 (12) ◽

pp. 753-767 ◽

Cited By ~ 5

Author(s):

Scott M. Tanner ◽

Joseph G. Daft ◽

Stephanie A. Hill ◽

Colin A. Martin ◽

Robin G. Lorenz

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

Cell Function ◽

Interleukin 17 ◽

Intestinal Tumor ◽

Double Positive ◽

Tumor Immunosurveillance ◽

T Cell Function ◽

Ifn Γ ◽

Cell Balance

The adenomatous polyposis coli ( APC) gene is a known tumor suppressor gene, and mice with mutations in Apc (ApcMin/+) spontaneously form multiple intestinal neoplasms. In this model of human colorectal cancer (CRC), it has been reported that CD4+ T-cell-derived interleukin 17 (IL-17) promotes intestinal tumor development, but it is not known if the Apc mutation actually directly alters T-cell function and subsequently tumor immunosurveillance. To investigate the ApcMin/+ mutation on T-cell function, flow cytometric, histochemical, and immunofluorescent studies on both wild-type (Apc+/+) and ApcMin/+ mice were performed. We identified decreased levels of interferon gamma (IFN-γ+)IL-17+ double-positive CD4+ cells in the mesenteric lymph nodes and Peyer’s patches of ApcMin/+ mice. In addition, altered levels of CD8+ cells, and changes in CD8+ production of IFN-γ and granzyme B were observed. These T-cell alterations did modify tumor immunosurveillance, as the adoptive transfer of splenocytes from ApcMin/+ animals into a chemically induced CRC model resulted in the inability to prevent epithelial dysplasia. These results suggest an altered T-cell balance in ApcMin/+ mice may disrupt intestinal homeostasis, consequently limiting intestinal tumor immunosurveillance.

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Modulation of PKM activity affects the differentiation of TH17 cells

Science Signaling ◽

10.1126/scisignal.aay9217 ◽

2020 ◽

Vol 13 (655) ◽

pp. eaay9217

Author(s):

Scott M. Seki ◽

Kacper Posyniak ◽

Rebecca McCloud ◽

Dorian A. Rosen ◽

Anthony Fernández-Castañeda ◽

...

Keyword(s):

T Cell ◽

Small Molecules ◽

Th17 Cells ◽

Cell Function ◽

Therapeutic Potential ◽

Interleukin 17 ◽

Gm Csf ◽

T Cell Function ◽

The Brain ◽

Tgf Β1

Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell–mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17–producing TH17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of TH17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.

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