Proteolytic processing of PD-L1 by ADAM proteases in breast cancer cells

In this study, we show that a portion of PD-L1 exogenously expressed in several triple-negative breast cancer cell lines, as well as endogenous PD-L1, is proteolytically cleaved by cell surface metalloproteases. The cleavage generates an  ~ 37-kDa N-terminal PD-L1 fragment that is released to the media and a C-terminal PD-L1 fragment that remains associated with cells but is efficiently eliminated by lysosomal degradation. We identify ADAM10 and ADAM17, two closely related members of the ADAM family of cell surface metalloprotea ses, as enzymes mediating PD-L1 cleavage. Notably, treatment of cells with ionomycin, a calcium ionophore and a known activator of ADAM10, or with phorbol 12-myristate 13-acetate, an activator of ADAM17, dramatically increases the release of soluble PD-L1 to the media. We postulate that ADAM10 and/o r ADAM17 may contribute to the regulation of the PD-L1/PD-1 pathway and, ultimately, to anti-tumor immunity in triple-negative breast cancer.
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

Related Links:

Major differences in the results of two separate studies with addition of immunotherapy in triple-negative breast cancer are making this space more complicated than clear, according to Dr Kathy Miller.Medscape Oncology
Source: Medscape Hematology-Oncology Headlines - Category: Cancer & Oncology Tags: Hematology-Oncology Commentary Source Type: news
This study is the first to investigate the immunogenicity of LDHC using T cells from healthy individuals. LDHC-specific T cell responses were induced by in vitro stimulation with synthetic peptides, or by priming with autologous peptide-pulsed dendritic cells. We evaluated T cell activation by IFN- γ ELISpot and determined cytolytic activity of HLA-A*0201-restricted T cells in breast cancer cell co-cultures. In vitro T cell stimulation induced IFN-γ secretion in response to numerous LDHC-derived peptides. Analysis of HLA-A*0201 responses revealed a significant T cell activation after stimula tion with peptide p...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
Publication date: Available online 10 January 2020Source: Nanomedicine: Nanotechnology, Biology and MedicineAuthor(s): Jamshid Gholizadeh Navashenaq, Parvin Zamani, Amin Reza Nikpoor, Jalil Tavakkol-Afshari, Mahmoud Reza JaafariAbstractMyeloid-derived suppressor cells (MDSCs) play a pivotal role in cancer. To overcome the problem of the MDSCs in the tumor microenvironment in this study, a combination of immunotherapy and chemotherapy was used. For this purpose, a liposomal formulation of P5 peptide and PEGylated liposomal doxorubicin (Doxil®) was utilized to treat mice bearing HER2+ tumor model. The results revealed th...
Source: Nanomedicine: Nanotechnology, Biology and Medicine - Category: Nanotechnology Source Type: research
Abstract The great success of immunotherapy is paving the way for a new era in cancer treatment and is driving major improvements in the therapy of patients suffering from a range of solid tumors. However, the choice of the appropriate tumor antigens to be targeted with cancer vaccines and T-cell therapies is still a challenge. Most antigens targeted so far have been identified on the tumor bulk and are expressed on differentiated cancer cells. The discovery of a small population of cancer stem cells (CSC), which is refractory to most current therapies and responsible for the development of metastasis and recurren...
Source: Seminars in Immunology - Category: Allergy & Immunology Authors: Tags: Semin Immunol Source Type: research
In conclusion, our analysis identifies genes signatures with potential to recognize immune activated ovarian and basal-like breast cancers with favorable prognosis and with a remarkable predictive capacity in tumors with low mutational burden. The presented results led to a hypothesis being formulated, but prospective clinical studies are needed to support a potential clinical application.
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
AbstractThe overall aim of this prospective study was to delineate the role of monocytic myeloid-derived suppressor cells (Mo-MDSCs) in patients with metastatic breast cancer (MBC). MDSCs are a heterogeneous group of immunosuppressive cells often enriched in different malignancies which hold prognostic and predictive value for clinical outcomes. Here, we assessed the clinical significance of Mo-MDSCs in 54 patients with de novo or distant recurrent MBC. We show that high levels of Mo-MDSCs significantly correlated with de novo MBC (metastatic disease at initial diagnosis), estrogen receptor (ER) negativity, and liver- and ...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
In this study, we evaluated the specification of a designed immunotoxin formed by EPHA2-specific scfv linked with PE38KDEL on EPHA2-overexpressing breast cancer cell line. This new scfv-based recombinant immunotoxin was studied in terms of features such as binding potency, cytotoxicity effects, apoptosis induction ability, and internalization. The flow cytometry results showed that the immunotoxin can significantly (approximately 99%) bind to EPHA2-overexpressing breast cancer cell line (MDA-MB-231) in a low concentration (2.5 ng/ul) while cannot significantly bind to the normal cell line (HEK-293) or even EPHA2-very low e...
Source: European Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharmacol Source Type: research
AbstractClinical progress in the field of HER2-positive breast cancer therapy has been dramatically improved by understanding of the immune regulatory mechanisms of tumor microenvironment. Passive immunotherapy utilizing recombinant monoclonal antibodies (mAbs), particularly trastuzumab and pertuzumab has proved to be an effective strategy in HER2-positive breast cancer treatment. However, resistance to mAb therapy and relapse of disease are still considered important challenges in clinical practice. There are increasing reports on the induction of cellular and humoral immune responses in HER2-positive breast cancer patien...
Source: Archivum Immunologiae et Therapiae Experimentalis - Category: Allergy & Immunology Source Type: research
Over the last few decades, the death rate from cancer dropped by 29% in the U.S., according to the latest data from the American Cancer Society (ACS). That, the ACS’s new study estimates, saved 2.9 million lives from 1991 to 2017, largely owing to declines in mortality from the four leading cancer types: lung, breast, prostate and colon. From 2016 to 2017—the latest year for which data are available—the overall cancer death rate declined by 2.2%, the largest single-year reduction ever recorded. These new figures were reported in a study published in CA: A Cancer Journal for Clinicians. The declines are a...
Source: TIME: Health - Category: Consumer Health News Authors: Tags: Uncategorized Cancer Source Type: news
Condition:   Breast Cancer Interventions:   Radiation: Stereotactic Body Radiation Therapy (SBRT) (50GY in 5 fractions);   Drug: Letrozole 2.5Mg Tab;   Drug: Palbociclib 125mg Sponsor:   Weill Medical College of Cornell University Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
More News: Allergy & Immunology | Breast Cancer | Calcium | Cancer | Cancer & Oncology | Immunotherapy | Study