Immunologic correlates in a CIC::DUX4 fusion-positive sarcoma responsive to dual immune checkpoint blockade

CIC::DUX4 sarcoma (CDS) is a rare and aggressive subtype of soft tissue sarcoma with poor prognosis and limited treatment options. Immunotherapy has not been studied in this disease. To our knowledge, response to immune checkpoint blockade (ICB) has not been previously reported. Here, we present the first case of a patient with CDS responding to dual ICB with nivolumab and relatlimab. Immunohistochemical (IHC) analysis of pre-treatment samples revealed minimal immune cell infiltration, with scarce CD3+, CD8+, and FOXP3+ T-cells and negligible expression of PD-L1 and PD-1 markers. Post-treatment tumor samples revealed a significant shift in the immune microenvironment, with increased CD8 + T-cell infiltration and co-expression of exhaustion markers PD-1 and LAG-3 following treatment. These findings suggest that doublet ICB can activate an antitumor immune response in CDS, overcoming the immune cold phenotype typically associated with this sarcoma. This case provides the first evidence of dual PD-1/LAG-3 blockade inducing an immune response in CDS. The favorable response and tolerability observed in this patient highlight the potential of dual ICB as a therapeutic option in CDS that merits further investigation.