Synovial sarcoma: characteristics, challenges, and evolving therapeutic strategies

: Synovial sarcoma (SS) is a rare and aggressive disease that accounts for 5%-10% of all soft tissue sarcomas. Although it can occur at any age, it typically affects younger adults and children, with a peak incidence in the fourth decade of life. In >95% of cases, the oncogenic driver is a translocation between chromosomes X and 18 that leads to the formation of the SS18::SSX fusion oncogenes. Early and accurate diagnosis is often a challenge; optimal outcomes are achieved by referral to a specialist center for diagnosis and management by a multidisciplinary team as soon as SS is suspected. Surgery with or without radiotherapy and/or chemotherapy can be effective in localized disease, especially in children. However, the prognosis in the advanced stages is poor, with treatment strategies that have relied heavily on traditional cytotoxic chemotherapies. Therefore, there is an unmet need for novel effective management strategies for advanced disease. An improved understanding of disease pathology and its molecular basis has paved the way for novel targeted agents and immunotherapies that are being investigated in clinical trials. This review provides an overview of the epidemiology and characteristics of SS in children and adults, as well as the patient journey from diagnosis to treatment. Current and future management strategies, focusing particularly on the potential of immunotherapies to improve clinical outcomes, are also summarized

How H13 histocompatibility peptides differing by a single methyl groug and lacking conventional MHC binding anchor motifs determine self-nonself discrimination.

The mouse H13 minor histocompatibility (H) Ag, originally detected as a barrier to allograft transplants, is remarkable in that rejection is a consequence of an extremely subtle interchange, P4(Val/Ile), in a nonamer H2-D(b)-bound peptide. Moreover, H13 peptides lack the canonical P5(Asn) central anchor residue normally considered important for forming a peptide/MHC complex. To understand how these noncanonical peptide pMHC complexes form physiologically active TCR ligands, crystal structures of allelic H13 pD(b) complexes and a P5(Asn) anchored pD(b) analog were solved to high resolution. The structures show that the basis of TCRs to distinguish self from nonself H13 peptides is their ability to distinguish a single solvent-exposed methyl group. In addition, the structures demonstrate that there is no need for H13 peptides to derive any stabilization from interactions within the central C pocket to generate fully functional pMHC complexes. These results provide a structural explanation for a classical non-MHC-encoded H Ag, and they call into question the requirement for contact between anchor residues and the major MHC binding pockets in vaccine design