Immunotherapy for sarcomas

Sarcomas are a heterogeneous group of malignancies of mesenchymal origin; their molecular and genomic mechanisms differ with regard to histology. These characteristics lead to the presentation of varied immunological profiles based on the tumor microenvironment. Various immunotherapies are considered for the treatment of sarcoma. These treatments are performed either in isolation or in combination with other methods such as cytotoxic chemotherapy or the use of molecular target agents. Among these, two recently emerging immunotherapies include T-cell receptor gene therapy and immune checkpoint inhibitor therapy, which are expected to be effective for many types of sarcoma. A sarcoma with a disease-specific translocation and a limited number of mutations, such as synovial sarcoma, expresses high levels of self-antigens, like the New York esophageal squamous cell carcinoma 1, which has been targeted in T-cell receptor gene therapy. On the other hand, sarcomas with a greater number of mutations, such as undifferentiated pleomorphic sarcomas, myxofibrosarcoma and dedifferentiated liposarcomas, can be good candidates for immune checkpoint inhibitors. Among immune checkpoint inhibitor therapies, programmed cell death-1 blockade (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte–associated antigen 4 blockade (ipilimumab) have been investigated most often in sarcoma. Although the sole use of immune checkpoint inhibitors provides limited efficacy, combined immunotherapy with immune checkpoint inhibitors or molecular target agents, especially antiangiogenic agents, has shown moderate results against some types of sarcoma, such as the alveolar soft part sarcoma. Several clinical trials utilizing immunotherapy, including T-cell receptor gene therapy and immune checkpoint inhibitors, in sarcomas are under progress. By clarifying the tumor microenvironment and biomarker-predictive capacity of immunotherapy in sarcomas, better clinical trials can be designed; this could lead to improved outcomes for immunotherapy in sarcoma.

Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes

Hypereosinophilia (HE) is a heterogeneous condition with a persistent elevated eosinophil count of >350/mm3, which is reported in various (inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. HE may be associated with tissue or organ damage and, in this case, the disorder is classified as hypereosinophilic syndrome (HES). Different studies have allowed for the discovery of two major pathogenetic variants known as myeloid or lymphocytic HES. With the advent of molecular genetic analyses, such as T-cell receptor gene rearrangement assays and Next Generation Sequencing, it is possible to better characterize these syndromes and establish which patients will benefit from pharmacological targeted therapy. In this review, we highlight the molecular alterations that are involved in the pathogenesis of eosinophil disorders and revise possible therapeutic approaches, either implemented in clinical practice or currently under investigation in clinical trials.

The RAG1 Ubiquitin Ligase Domain Enhances T Cell Receptor Gene Assembly and Thymic Selection

RAG1/RAG2 (RAG) endonuclease-mediated assembly of diverse lymphocyte antigen receptor genes by V(D)J recombination is critical for the development and immune function of T and B cells. However, this process creates highly self-reactive cells that must be negatively selected to suppress autoimmunity. The RAG1 protein contains a ubiquitin ligase domain that stabilizes RAG1 and stimulates RAG endonuclease activity. We report here that mice lacking RAG1 ubiquitin ligase activity exhibit diminished recombination of T cell receptor (TCR) b and a loci, and impaired thymocyte developmental transitions that require the assembly of these genes and signaling by their proteins. The mice also have reduced expression of TCR signaling proteins within thymocytes, less efficient negative selection of highly self-reactive thymocytes, and mature ab T cells of elevated autoimmune potential. Thus, we propose that the RAG1 ubiquitin ligase domain provides ab T cell developmental stage-specific means to augment TCR signaling and thereby enhance selection for beneficial TCR genes and against ab TCRs possessing high autoimmune potential.

Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder: Case series at the Semmelweis University, Department of Dermatology, Venereology and Dermatooncology and review of the literature

In the updated 2018 WHO-EORTC classification, the name of the disease was changed to primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder instead of the former primary cutaneous CD4+ small/medium T-cell lymphoma, because of its indolent behaviour and uncertain malignant potential. The authors present five cases of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, through which they show the various clinical appearances, and the histological features of the disease, and review the literature. The authors point out that the disease, except for a few cases, presented with a solitary lesion, has a particularly good prognosis, remains localized and shows a tendency to regress despite the monoclonal T-cell receptor gene rearrangement.