Soft tissue sarcomas are therapeutically challenging. Among soft tissue sarcoma subtypes, undifferentiated pleomorphic sarcoma (UPS) exhibits one of the most pronounced disparities between its comparatively higher responsiveness to immunotherapy and its limited responsiveness to conventional cytotoxic chemotherapy. The interplay between immunotherapy and cytotoxic chemotherapy is still largely unknown. Interferon-γ (IFNγ) is a key player in antitumor immunity and contributes to the modulation of the tumor microenvironment, which impacts both immune and cancer cells. The mechanism by which this interplay can affect cancer cell chemosensitivity and immune sensitivity is difficult to predict. The present study aimed to investigate the interplay of IFNγ signaling in the UPS cell line JBT19. It was identified that IFNγ treatment significantly decreased the proliferation of JBT19 cells and increased the surface expression levels of cluster of differentiation (CD)44, CD47, CD95 (Fas), major histocompatibility complex (MHC)-I and programmed death-ligand 1 (PD-L1). In addition, IFNγ strongly upregulated surface expression levels of MHC-II and converted JBT19 cells into docetaxel-resistant cells. The IFNγ-induced changes were sustained but reversible after 3 weeks of cell culture without IFNγ. Regardless of IFNγ treatment, JBT19 cells could elicit and amplify the adaptive immune response in vitro. The in vitro JBT19-reactive lymphocytes effectively eliminated both IFNγ-treated and non-treated JBT19 cells, thus overcoming IFNγ-induced chemoresistance. To the best of our knowledge, the present study demonstrated a dual role of IFNγ towards cancer cell chemoresistance and immunostimulatory potential for the first time. The present study findings may have potential implications for combining immunotherapy with cytotoxic chemotherapy in cancer treatment in the future.

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital Motol 150 06 Prague Czech Republic

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