Tuftsin-tailored fusion protein inhibits the growth of circulating gastric tumor cells associated with macrophage phagocytosis

Circulating tumor cells (CTCs) are a major cause of tumor metastasis and resistance to anticancer therapies. To date, no effective low-toxicity chemotherapeutic agents or antibodies have exhibited significant clinical activity against CTCs. Macrophages are important mediators of antitumor immunity. Tuftsin (TF), a tetrapeptide located at residues 289–292 of the CH2 domain of the Fc region of the IgG heavy chain, binds to Nrp-1, a receptor on the surface of macrophages that promotes phagocytosis and induces nonspecific activation of the immune system against tumors. Lidamycin (LDM) is an antitumor chemotherapy agent that is strongly cytotoxic to tumors and can dissociate into an apoprotein (LDP) and active enediyne (AE) in vitro. We previously constructed the fusion protein LDP-TF through genetic engineering and inserted the chromophore AE to produce LDM-TF, which can target macrophages to promote their phagocytic and cytotoxic activity against tumor cells. Preliminary experiments confirmed the anti-tumor activity of LDM-TFs. In this study, we found that LDM-TF effectively inhibited the growth of CTCs of gastric cancer origin and enhanced macrophage phagocytosis both in vivo and in vitro. Tumor cell expression of CD47, which helps to evade phagocytosis by macrophages, was substantially downregulated by LDM-TF. Notably, our in vitro experiments demonstrated that the combination of LDM-TF and anti-CD47 antibodies promoted phagocytosis more than either component alone. Our findings demonstrate the significant inhibitory effect of LDM-TF on the growth of CTCs of gastric cancer origin and suggest that the combination of LDM-TF and anti-CD47 antibodies may exhibit synergistic effects, thereby providing a new option for the clinical treatment of patients with advanced tumors that have metastasized

Minimum absolute lymphocyte counts during radiation are associated with a worse prognosis in patients with unresectable hepatocellular carcinoma

Background: Peripheral blood lymphocytes play an important role in antitumour immunity. We examined the relationship between the minimum absolute lymphocyte counts (Min ALCs) during radiotherapy (RT) and clinical outcomes in patients with hepatocellular carcinoma (HCC). Methods: Data from a total of 69 HCC patients who had received RT were retrospectively analysed. Peripheral blood lymphocytes were measured before RT, weekly during RT and after RT. Regression and mixed-effect models were used to assess the relationships with and potential predictors of overall survival (OS). Receiver-operating characteristic (ROC) curve analysis was used to define optimal cut-off points of continuous variables for outcomes. Results: The median follow up was 30 months (range, 4–68 months). The median survival time (MST), 1-year OS rate and 2-year OS rate of the whole group were 25 months, 51% and 39%, respectively. The average circulating lymphocyte counts declined during RT (1493.19 versus 503.48 cells/µl, p 450 cells/µl), respectively ( p < 0.001). After adjusting for potential confounders, multivariate Cox regression analysis demonstrated that Min ALC independently predicted patients’ OS (HR, 0.32; 95% CI, 0.15–0.69). Conclusions: Lower Min ALCs during RT may act as a worse prognostic factor for HCC after RT