scholarly journals Tet2 inactivation enhances the anti-tumor activity of tumor-infiltrating lymphocytes (TILs) to curtail melanoma growth

2020 ◽  
Author(s):  
Minjung Lee ◽  
Jianfang Li ◽  
Shaohai Fang ◽  
Joanna Zhang ◽  
Anh Vo ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Infiltrating Lymphocytes ◽  
Chromatin Accessibility ◽  
Rna Seq ◽  
Tumor Microenvironments ◽  
Tumor Onset ◽  
Infiltrating Lymphocytes ◽  
Anti Tumor Activity

Abstract Inactivation of tumor infiltrating lymphocytes (TILs) is one of the mechanisms mitigating anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further revealed that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs, and that Tet2 inactivation could benefit anti-tumor immunity to boost tumor suppression.

scholarly journals Tet2 Inactivation Enhances the Anti-Tumor Activity of Tumor-Infiltrating Lymphocytes (TILs) to Curtail Melanoma Growth

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-27
Author(s):  
Minjung Lee ◽  
Jianfang Li ◽  
Shaohai Fang ◽  
Joanna Zhang ◽  
Anh Tran Tram Vo ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Tumor Infiltrating Lymphocytes ◽  
Chromatin Accessibility ◽  
Tumor Microenvironments ◽  
Tumor Onset ◽  
Infiltrating Lymphocytes ◽  
Anti Tumor Activity

Inactivation of tumor infiltrating lymphocytes (TILs) is one of the mechanisms mitigating anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further revealed that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs, and that Tet2 inactivation could benefit anti-tumor immunity to boost tumor suppression. Disclosures No relevant conflicts of interest to declare.

scholarly journals Superpixel Image Segmentation of VISTA Expression in Colorectal Cancer: Implications for Immunotherapy

2020 ◽  
Author(s):  
Dongling Wu ◽  
Sean Hacking ◽  
Taisia Vitkovski ◽  
Mansoor Nasim
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Image Segmentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Stage ◽  
Infiltrating Lymphocytes ◽  
Patient Enrollment

Abstract Colorectal cancer is an overall bad player and accounts for 9% of all cancers. Today, advancements in immune checkpoint inhibition has provided therapeutics for many, but not all cancer patients. This issue is in part due to the tumoral microenvironment; which plays a significant role in determining response to immune check point therapeutics. This study serves as the first to evaluate a potent inhibitory checkpoint: V-domain immunoglobulin suppressor of T cell activation (VISTA) and its role in CRC. This was evaluated with both conventional light microscope and superpixel image segmentation. Here we found VISTA expression to be associated with low tumor budding, lower tumor stage, high tumor infiltrating lymphocytes, mature stromal differentiation, BRAF mutation status and better disease-free survival in colorectal cancer. When comparing methodologies; superpixel image segmentation better stratified patients into prognostic groups. Anti-VISTA clinical trials are now open and recruiting for patient enrollment for patients with certain advanced solid tumors. Considering raised VISTA expression is associated with improved survival for patients with colorectal cancer: careful, well-designed and robust clinical trials should be pursued in this cancer subtype.

scholarly journals Human Cancer Immunotherapy with PD-1/PD-L1 Blockade

2015 ◽  
Vol 7s2 ◽  
pp. BIC.S29325 ◽  
Author(s):  
Peilin Zheng ◽  
Zhiguang Zhou
Keyword(s):  
Clinical Trials ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Short Review ◽  
Programmed Cell Death 1 ◽  
Antitumor Immunotherapy ◽  
Tumor Types ◽  
Infiltrating Lymphocytes

The ligation of programmed cell death-1 (PD-1) to its ligands PD-L1 and PD-L2 counteracts T-cell activation, which is critical in immune tolerance. The persistent high expression of PD-1 and PD-L1 are also observed on tumor-infiltrating lymphocytes and various tumor cells, maintaining the highly suppressive microenvironment in tumor sites and promoting tumor malignancies. The blockade of PD-1 axis with PD-L2 fusion protein or monoclonal antibodies against either PD-1 or PD-L1 has been clinically evaluated in various tumor types. This short review summarizes the progress of PD-1 axis blockade in clinical trials to evaluate its effectiveness in the antitumor immunotherapy.

PD-1/PDL-1 Inhibitors as Immunotherapy for Ovarian Cancer

2018 ◽  
Author(s):  
Scott Moerdler ◽  
Xingxing Zang
Keyword(s):  
Ovarian Cancer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Escape ◽  
Tumor Infiltrating Lymphocytes ◽  
Immunoglobulin Superfamily ◽  
Combination Therapies ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Infiltrating Lymphocytes

Programmed death 1 (PD-1), a member of the B7-CD28 immunoglobulin superfamily, and its ligands PD-L1/PD-L2 inhibit T-cell activation. They also play a key role in the tumor microenvironment, allowing for cancer immune escape. PD-1 is induced on a variety of immune cells, including tumor-infiltrating lymphocytes (TILs), while PD-L1 is found on many types of solid tumors including ovarian cancer and some TILs. The use of immunocheckpoint inhibitors like anti-PD-1 and anti-PD-L1 therapies has been shown to reactivate the immune system to attack tumor cells. Ovarian cancers have been shown to be responsive to anti-PD-1 and anti-PD-L1 therapies, though immunocheckpoint inhibitors are not enough. Current research is evaluating combination therapies to improve response rates.

Association of minimally invasive colorectal resection with elevated levels of plasma B7 homolog 1 (B7-H1) during the first month after surgery and effect on immune suppression and growth of residual metastases.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 602-602
Author(s):  
Hmc Shantha Kumara ◽  
Erica Pettke ◽  
Carl S Winkler ◽  
Sandhu K Jaspreet ◽  
Xiaohong Yan ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Infiltrating Lymphocytes ◽  
Wilcoxon Test ◽  
Intestinal Epithelial ◽  
The Mean ◽  
Infiltrating Lymphocytes ◽  
Cell Effector Function ◽  
Cell Effector

602 Background: The co-stimulatory molecule B7 homolog 1 (B7-H1) is a ligand for PD-1 which is an immunoinhibitory receptor of activated lymphocytes. PD-1 expression is upregulated on tumor infiltrating lymphocytes (TILs), and B7-H1 expressed on cancer cells may inhibit T-cell activation and proliferation. B7-H1 is also expressed on endothelial (EC) and intestinal epithelial cells as well as activated macrophages. B7H1 in EC is rapidly induced by IFN-gamma and TNF. B7-H1 silencing with siRNA inhibits tumor cell proliferation/invasion. B7H1 expression in keratinocytes (KC) directly downregulates CD8(+) T-cell effector function via PD-1 binding at sites of inflammation. Shed B7-H1 can be found in the blood. Surgery’s impact on plasma B7H1 levels is unknown. This study’s purpose was to evaluate plasma B7H1 levels during the first month after MICR for colorectal (CRC). Methods: MICR CRC patients in an IRB approved data/plasma bank with adequate plasma available were eligible. Clinical and pathological data were reviewed. Blood samples were collected preoperatively (PreOp) and at 6 post-operative (Postop) time points (POD 1, 3, 7-13, 14-20, 21-27, 28-41). B7-H1 levels were analyzed in duplicate using ELISA. The Wilcoxon test was used for analysis. Results: 88 CRC patients who had a MICR met inclusion criteria (28% rectal and 62% colon lesions). The mean PreOp B7-H1 level was 51.9±20.9 pg/ml. Significantly elevated mean plasma levels were noted on POD1 (64.9±24.2 pg/ml, n = 86, p = < 0.0001), POD3 (67.3±24.6 pg/ml, n= 72, p = < 0.0001), POD7-13 (69.2±22.6 pg/ml, n = 65, p = < 0.0001), POD14-20 (72.5±28.9 pg/ml, n=23,p=0.001), POD 21-27 (79.4±66.6 pg/ml, n = 13, p = 0.001), and on POD 28-41 (56.3 ±22.7 pg/ml, n = 20, p =0.02), when compared to PreOp levels. Conclusions: Plasma B7-H1 levels are elevated for over a month after MICR for CRC. The etiology of the early increase may be the acute inflammatory response whereas late elevations may be related to wound healing-related tissue remodeling. Elevated plasma B7-H1 may suppress TIL’s which may result in increased tumor growth. Further studies are warranted.

scholarly journals Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion

2018 ◽  
Vol 41 (9) ◽  
pp. 399-405 ◽  
Author(s):  
René J. Tavera ◽  
Marie-Andrée Forget ◽  
Young Uk Kim ◽  
Donastas Sakellariou-Thompson ◽  
Caitlin A. Creasy ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes
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