Epigenetic focus on angioimmunoblastic T-cell lymphoma: pathogenesis and treatment.

PURPOSE OF REVIEW: Angioimmunoblastic T-cell lymphoma (AITL) is a frequent peripheral T-cell lymphoma affecting elderly patients with a poor outcome when treated with conventional chemotherapy. Molecular studies revealed a homogenous mutational landscape gathering anomalies in genes regulating the DNA methylation and hydroxymethylation and anomalies in T-cell signalling. RECENT FINDINGS: Recent studies indicate that AITL emerges from a TET2 and/or DNMT3A mutated clonal haematopoiesis. This clonal haematopoiesis bearing mutations altering DNA hydroxymethylation can explain the observed coexistence of AITL with myeloid neoplasms. In addition, AITL development requires AITL-specific mutations, such as the RHOAG17V mutations. Combination of TET2 and RHOAG17V alterations results in the development of AITL-like disease in mouse models. The impact of the presence of these mutations on patient outcome seems limited and new biological factor predicting treatment response and survival remains to be determined. At the therapeutic level, therapies targeting epigenetic changes, such as histone deacetylase inhibitors and the hypomethylating 5-azacytidine agent, could have efficacy in this disease and gave promising results. Recent progress in mouse model development should allow development of new treatments. SUMMARY: Epigenetic changes are frequent in AITL and could be a promising target.

Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma.

Cancer metabolic reprogramming has been recognized as one of the cancer hallmarks that promote cell proliferation, survival, as well as therapeutic resistance. Up-to-date regulation of metabolism in T-cell lymphoma is poorly understood. In particular, for human angioimmunoblastic T-cell lymphoma (AITL) the metabolic profile is not known. Metabolic intervention could help identify new treatment options for this cancer with very poor outcomes and no effective medication. Transcriptomic analysis of AITL tumor cells, identified that these cells use preferentially mitochondrial metabolism. By using our preclinical AITL mouse model, mimicking closely human AITL features, we confirmed that T follicular helper (Tfh) tumor cells exhibit a strong enrichment of mitochondrial metabolic signatures. Consistent with these results, disruption of mitochondrial metabolism using metformin or a mitochondrial complex I inhibitor such as IACS improved the survival of AITL lymphoma-bearing mice. Additionally, we confirmed a selective elimination of the malignant human AITL T cells in patient biopsies upon mitochondrial respiration inhibition. Moreover, we confirmed that diabetic patients suffering from T-cell lymphoma, treated with metformin survived longer as compared to patients receiving alternative treatments. Taking together, our findings suggest that targeting the mitochondrial metabolic pathway could be a clinically efficient approach to inhibit aggressive cancers such as peripheral T-cell lymphoma.

Novel T Follicular Helper-like T-Cell Lymphoma Therapies: From Preclinical Evaluation to Clinical Reality.

The classification of peripheral T-cell lymphomas (PTCL) is constantly changing and contains multiple subtypes. Here, we focus on Tfh-like PTCL, to which angioimmunoblastic T-cell lymphoma (AITL) belongs, according to the last WHO classification. The first-line treatment of these malignancies still relies on chemotherapy but gives very unsatisfying results for these patients. Enormous progress in the last decade in terms of understanding the implicated genetic mutations leading to signaling and epigenetic pathway deregulation in Tfh PTCL allowed the research community to propose new therapeutic approaches. These findings point towards new biomarkers and new therapies, including hypomethylating agents, such as azacytidine, and inhibitors of the TCR-hyperactivating molecules in Tfh PTCL. Additionally, metabolic interference, inhibitors of the NF-κB and PI3K-mTOR pathways and possibly novel immunotherapies, such as antibodies and chimeric antigen receptors (CAR) directed against Tfh malignant T-cell surface markers, are discussed in this review among other new treatment options.

Current Approaches in Development of Immunotherapeutic Vaccines for Breast Cancer.

Cancer is the leading cause of death worldwide. In developed as well as developing countries, breast cancer is the most common cancer found among women. Currently, treatment of breast cancer consists mainly of surgery, chemotherapy, hormone therapy, and radiotherapy. In recent years, because of increased understanding of the therapeutic potential of immunotherapy in cancer prevention, cancer vaccines have gained importance. Here, we review various immunotherapeutic breast cancer vaccines including peptide-based vaccines, whole tumor cell vaccines, gene-based vaccines, and dendritic cell vaccines. We also discuss novel nanotechnology-based approaches to improving breast cancer vaccine efficiency.