Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge as a highly lethal malignancy, anticipated to rise to the rank of second-leading cause of cancer-related mortality by 2030. Despite this alarming trend, effective treatment options for PDAC remain elusive. Surgical resection, the primary curative intervention for PDAC, is only feasible in ~20% of patients and has a high recurrence rate. Traditional cancer therapies, such as chemotherapy and radiation therapy, have demonstrated limited efficacy against PDAC.In recent years, immunotherapies have shown promise in various cancer types. However, their effectiveness as standalone treatments for PDAC has been hindered by the desmoplastic stromal response characteristic of PDAC tumors. This stromal reaction involves a complex interplay between tumor cells and various stromal cell types, creating an immunosuppressive tumor microenvironment (iTME) that excludes cytotoxic T cells and inhibits anti-tumor immune responses. The complexity of the stromal compartment in PDAC remains inadequately understood, encompassing questions regarding its diverse composition, intricate interplay between stromal compartments, functional implications in fostering immunotherapy resistance, and the underlying mechanistic regulation within PDAC. Thus, a comprehensive dissection of stromal composition, function, and regulation is imperative.
To address the questions raised above, this study aimed to elucidate the role of epigenetic regulation in shaping the iTME of PDAC. Using single-cell sequencing techniques, we identified distinct populations of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs) with immunosuppressive potential and demonstrated that their immunosuppressive functions were disrupted by pharmacological BET inhibitors (BETi), which preferentially block super enhancer driven gene expression. Moreover, by disrupting the immunosuppressive TME, we found that BETi could enhance the efficacy of immune checkpoint blockade, promoting anti-tumor T cell responses mediated by the IFNγ-CXCL9/10 axis. This discovery laid the groundwork for our development of a novel therapeutic strategy utilizing nanoparticle-conjugated BETi to improve tumor drug delivery and reduce systemic toxicity.
Furthermore, our investigations into the immunosuppressive mechanisms of the TME unveiled the ability of stromal signals to reprogram tumor cells and promote their resistance to T cell-mediated cytotoxicity. By developing an antigen-specific tumor killing platform, we demonstrated that soluble factors present in tumor interstitial fluid (TIF) could induce a transcriptional profile associated with immune evasion in tumor cells. This transcriptional program is regulated, in part, by stroma-induced NFκB activation. In vivo studies targeting NFκB-regulated immunosuppressive genes, including COX2 and LIF, suggest that disrupting this pathway could be a promising avenue for enhancing immunotherapy responses in PDAC driven by antigen-specific T cell killing, such as CAR-T cell therapy.
In summary, this study not only facilitates a deeper comprehension of the underlying causes of current therapeutic shortcomings in PDAC, but also paves the way for the development of innovative strategies aimed at targeting immune resistance mechanisms and sensitizing PDAC to immunotherapies.
