These data suggest ICD induction also in our model system. Therefore, we measured two gold standard in vitro ICD markers, secretion of ATP and release of HMGB1 21, and found that FTD significantly and dose-dependently increased both extracellular ATP (Fig. FTD has previously been shown to induce ICD in various human CRC cell lines in vitro 15. ![]() ![]() 1A) and increased apoptosis (Annexin V) (Fig. Treatment with FTD or OXP for 72 h effectively decreased viability (indirectly measured as GFP signal) (Fig. Treatment response and ICD induction of FTD and positive control oxaliplatin (OXP) were evaluated in the CRC cell line HCT116-GFP, cultured as monoculture or co-cultured with human PBMCs stimulated with anti-CD3 and IL-2. Trifluridine induces the release of ICD markers and secretion of pro-inflammatory cytokines in vitro ScRNA-seq recapitulated major mechanisms of action previously described for FTD and provided new insight into possible treatment-induced effects on T-cell mediated antitumor responses. To address this and to learn more about the impact of FTD on both cancer- and immune cells, we co-cultured the human CRC cell line HCT116 with peripheral blood mononuclear cells (PBMCs) and used Single-Cell 3′ RNA sequencing (scRNA-seq) to analyze posttreatment gene expression profiles in thousands of individual cancer and immune cells concurrently. However, there is a lack of studies exploring drug effects in co-cultures of tumor and immune cells using this technique. Today, sequencing with single-cell resolution enables thorough evaluation of heterogeneous responses across multiple cell types and subsets of cell populations simultaneously 18, 19, 20. Until recently each cell type of interest had to be sequenced separately and with bulk expression profiles as a read-out. Gene expression profiles are a highly informative phenotypic measure of treatment response 16, 17. did however demonstrate that FTD is capable of inducing ICD in various human CRC cell lines in vitro 15. Thus far, not much is known about the immunological effects of FTD, a recent study by Limagne et al. The nucleoside analogue trifluridine (FTD) is the active component of TAS-102 an antitumor drug first approved for treatment of metastatic colorectal cancer (mCRC) in Japan 2015 13, 14. Today, oxaliplatin is an acknowledged ICD inducer 10 and this property has been demonstrated both in preclinical 11 and clinical settings 12. ICD is a form of regulated cell death (RCD) capable of activating an adaptive immune response by provoking the release of damage-associated molecular patterns (DAMPs) 9. The concept of immunogenic cell death (ICD) induced by antineoplastic agents has gained increasing interest 6. Taken together, it has become evident that treatment outcome is dictated by the combined effect on both cancer- and immune cells 3, 5, making it crucial to improve our knowledge regarding the interplay between chemotherapeutic agents and the immune system. Furthermore, clinical data indicate that FOLFOX treatment results in higher overall survival rates 8, potentially linked to its favorable immunoregulatory effect 6. Preclinical data suggest that FOLFOX reduces immunosuppression while FOLFIR augments immunosuppression 7. For a long time, it was assumed that chemotherapy had only immunosuppressive adverse effects on the immune system however, this viewpoint has shifted as certain chemotherapeutics have been shown to enhance tumor-specific immune responses 5, 6. ![]() ![]() FDA approved protocols include FOLFOX (5-fluorouracil + oxaliplatin) and FOLFIRI (5-fluorouracil + irinotecan) 4. CRC is commonly treated using combined chemotherapies. Additionally, many of the antineoplastic agents used today have adverse effects further suppressing the already challenged immune cells 2, 3. Progression of colorectal cancer (CRC), as well as many other tumors, involve changes in the tumor microenvironment (TME) toward immunosuppression and loss of immunosurveillance 1.
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