Tumor genetic alterations and features of the immune microenvironment drive myelodysplastic syndrome escape and progression

This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34+ blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

Related Links:

In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients. Introduction DNA methyltransferase inhibitors (DNMTi) are widely used as chemical tools for hypomethylating the genome, with an aim to understand the role of DNA methylation in multiple processes (e.g., X-chromosome inactivation and DNA imprinting) and as an anti-ca...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Markus Hartl* and Rainer Schneider Center of Molecular Biosciences (CMBI), Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria The neuronal proteins GAP43 (neuromodulin), MARCKS, and BASP1 are highly expressed in the growth cones of nerve cells where they are involved in signal transmission and cytoskeleton organization. Although their primary structures are unrelated, these signaling proteins share several structural properties like fatty acid modification, and the presence of cationic effector domains. GAP43, MARCKS, and BASP1 bind to cell membrane phospholipids, a process reversibly regulate...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
This study demonstrated that the incidence of ischemic heart disease and death were three times higher among men with low birth weight compared to men with high birth weight (5). Epidemiological investigations of adults born at the time of the Dutch famine between 1944 and 1945 revealed an association between maternal starvation and a low infant birth weight with a high incidence of hypertension and coronary heart disease in these adults (23). Furthermore, Painter et al. reported the incidence of early onset coronary heart disease among persons conceived during the Dutch famine (24). In that regard, Barker's findin...
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research
Our group developed a 161533 trispecific killer engager (TriKE) molecule to target acute myeloid leukemia (AML) cells using Natural Killer (NK) cells. This molecule contains an anti-CD16 camelid nanobody to activate NK cells, an anti-CD33 single chain variable fragment (scFv) to engage cancer targets, and an IL-15 molecule that drives NK cell priming, expansion and survival. Using an earlier version of this molecule, we have shown that the CD33 TriKE is effective at activating NK cells against AML targets in vitro and in vivo. This preclinical data has lead to the establishment of a clinical trial in refractory AML patient...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I Source Type: research
Conclusions:In this study, targeted RNA-seq is shown as effective and accurate tool to detect weakly expressed transcripts as CTAs. In this work, TFDP3 and DDX53, validated at proteomic level, emerge as most promising candidates for immunotherapy in combination with hypomethylating agents in MDS patients.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - Category: Hematology Authors: Tags: 636. Myelodysplastic Syndromes-Basic and Translational Studies: Poster III Source Type: research
ConclusionsOur preliminary data demonstrate that NB patients at risk of developing secondary leukemia can be identified by molecular profiling of BM aspirates obtained during routine disease surveillance for NB. These findings present an opportunity for the development of early detection studies for patients with pediatric malignancies undergoing intensive therapy and importantly inform studies into mechanisms of leukemic transformation and specific gene-treatment effects.DisclosuresCheung: Ymabs: Patents &Royalties.
Source: Blood - Category: Hematology Authors: Tags: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis II Source Type: research
Abstract Niraparib is an oral poly(ADP ribose) polymerase (PARP) inhibitor that is currently approved by the United States Food and Drug Administration (US FDA) as well as recently approved by the European Medicines Agency (EMA) for the maintenance treatment of women with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. The mechanisms of action of niraparib include inhibition of PARP enzymatic activity as well as increased formation of PARP-DNA complexes through "trapping" the PARP enzyme on damaged DNA. Phase I and III studies have demonstrated activity an...
Source: Gynecologic Oncology - Category: Cancer & Oncology Authors: Tags: Gynecol Oncol Source Type: research
Abstract: Targeting DNA hypermethylation, using nucleoside analogs, is an efficient approach to reprogram cancer cell epigenome leading to reduced proliferation, increased differentiation, recognition by the immune system, and ultimately cancer cell death. DNA methyltransferase inhibitors have been approved for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myelogenous leukemia. To improve clinical efficacy and overcome mechanisms of drug resistance, a second generation of DNA methyltransferase inhibitors has been designed and is currently in clinical trials. Although efficient in mo...
Source: The Cancer Journal - Category: Cancer & Oncology Tags: Review Articles Source Type: research
Abstract Targeting DNA hypermethylation, using nucleoside analogs, is an efficient approach to reprogram cancer cell epigenome leading to reduced proliferation, increased differentiation, recognition by the immune system, and ultimately cancer cell death. DNA methyltransferase inhibitors have been approved for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myelogenous leukemia. To improve clinical efficacy and overcome mechanisms of drug resistance, a second generation of DNA methyltransferase inhibitors has been designed and is currently in clinical trials. Although efficie...
Source: Cancer Journal - Category: Cancer & Oncology Authors: Tags: Cancer J Source Type: research
DiscussionAlthough phenotypically defined CTL numbers were increased in the bone marrow of MDS patients, we found that CTL from high-risk MDS patients exhibited a lower TCR-induced redirected cytotoxic capacity. Thus, decreased T cell cytotoxicity seems related to reduced adhesion to target cells and may contribute to impaired anti-leukemic immune surveillance in MDS.
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
More News: Acute Leukemia | Acute Myeloid Leukemia | Allergy & Immunology | Cancer | Cancer & Oncology | Genetics | Immunotherapy | Leukemia | Myelodysplastic Syndrome | Study