Human c-SRC kinase (CSK) overexpression makes T cells dummy

AbstractAdoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide –MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on corre ct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the majority of the adverse events are due to TCR recognition of the wrong target, we tested if blocking the signalling would affect the binding. By over-expressing the c-SRC kinase (CSK), a negative regu lator of LCK, in redirected T cells, we showed that peripheral blood T cells inhibited anti-CD3/anti-CD28-induced phosphorylation of ERK, whereas TCR proximal signalling was not affected. Similarly, overexpression of CSK together with a therapeutic TCR prevented pMHC-induced ERK phosphorylation. Dow nstream effector functions were also almost completely blocked, including pMHC-induced IL-2 release, degranulation and, most importantly, target cell killing. The lack of effector functions contrasted with the unaffected TCR expression, pMHC recognition, and membrane exchange activity (trogocytosis) . Therefore, co-expression of CSK with a therapeutic TCR did not compr...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

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Canonical WNT/β-catenin signaling is involved in most of the mechanisms that lead to the formation and development of cancer cells. It plays a central role in three cyclic processes, which are the cell division cycle, the immune cycle, and circadian rhythms. When the canonical WNT pathway is upregulated as in cancers, the increase in β-catenin in the nucleus leads to activation of the expression of numerous genes, in particular CYCLIN D1 and cMYC, where the former influences the G1 phase of the cell division cycle, and the latter, the S phase. Every stage of the immune cycle is disrupted by the canonical WNT sign...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
AbstractPurpose of ReviewT cell lymphoproliferative disorders represent a diverse group of hematologic malignancies with poor prognosis underscoring the need for novel therapeutic approaches. Disruption of the JAK/STAT signaling pathway has been described in this group of blood cancers and may represent an approach for targeted therapy. Here, we summarize the current data describing the disruptions of JAK/STAT signaling in T cell malignancies and focus on the existing evidence for exploitation of this pathway with targeted therapies.Recent FindingsTo date, preclinical studies have demonstrated the efficacy of JAK/STAT inhi...
Source: Current Hematologic Malignancy Reports - Category: Hematology Source Type: research
ConclusionsSmall sub-sets of breast cancers with high TMB exist and may present an opportunity for effective immunotherapeutic targeting.
Source: Targeted Oncology - Category: Cancer & Oncology Source Type: research
Bladder cancer (BC) is the most common neoplasia of the urothelial tract. Due to its high incidence, prevalence, recurrence and mortality, it remains an unsolved clinical and social problem. The treatment of BC is challenging and, although immunotherapies have revealed potential benefit in a percentage of patients, it remains mostly an incurable disease at its advanced state. Epigenetic alterations, including aberrant DNA methylation, altered chromatin remodeling and deregulated expression of non-coding RNAs are common events in BC and can be driver events in BC pathogenesis. Accordingly, these epigenetic alterations are n...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
ConclusionsOnly 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this.
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
Conclusion: This review is focused not only on the mechanism by which the immune system protects us but also on the ways in which it can inflict the body and how to modulate it with therapy. Thus, understanding the interaction of a tumor with the immune system provides insights into mechanisms that can be utilized to elicit anti-tumor immune responses. Here, we have recapitulated the function of the tumor microenvironment and immune checkpoints.
Source: Current Cancer Therapy Reviews - Category: Cancer & Oncology Source Type: research
Abstract BACKGROUND: Treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with programmed cell death protein 1 (PD-1) inhibitors has been associated with risk of developing immune-mediated adverse reactions (IMARs). OBJECTIVES: This review provides nurses with an overview of the safety of PD-1 inhibitors approved by the U.S. Food and Drug Administration for recurrent or metastatic SCCHN following platinum chemotherapy, as well as recommendations for assisting with the diagnosis and management of IMARs. METHODS: PubMed® searches were conducted to iden...
Source: Clinical Journal of Oncology Nursing - Category: Nursing Authors: Tags: Clin J Oncol Nurs Source Type: research
Immunotherapy drugs have so far produced underwhelming results in prostate cancer. Now a team of researchers may have figured out why and how to make these drugs work for prostate cancer patients.
Source: Forbes.com Healthcare News - Category: Pharmaceuticals Authors: Source Type: news
AbstractGall bladder carcinoma (GBC) is a worldwide problem, with a higher incidence in areas of the world where cholelithiasis is common. As GBC is usually diagnosed in an advanced stage, the mortality is high. An understanding of the molecular pathways of carcinogenesis and the mutations involved in the development and progression of GBC could be useful in early diagnosis. Understanding molecular markers of prognosis as well as predictors of outcome could also potentially benefit patients undergoing treatment. New therapies targeting major molecular pathways and immunotherapy are exciting novel therapeutic options. This ...
Source: Indian Journal of Surgical Oncology - Category: Cancer & Oncology Source Type: research
Date: Friday, 12 06, 2019; Speaker: Greg M Delgoffe, Associate Professor, Department of Immunology , University of Pittsburgh; Building: Building 10 (Clinical Center); Lipsett Amphitheater
Source: NIH Calendar of Events - Category: American Health Source Type: events
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