An ideal tumor treatment is supposed to eliminate the primary tumor and simultaneously trigger the host antitumor immune responses to prevent tumor recurrence and metastasis. Herein, a liposome encapsulating phosphoinositide 3-kinase gamma (PI3K ) inhibitor IPI-549 and photosensitizer chlorin e6 (Ce6), denoted by LIC, is prepared for colon cancer treatment. LIC internalized into CT26 cells generates reactive oxygen species (ROS) under laser irradiation to cause immunogenic tumor cell death, during which immunostimulatory signals such as calreticulin are released to further induce T lymphocyte-mediated tumor cell killing. Meanwhile, IPI-549 transported by liposome can inhibit PI3K in the myeloid-derived suppressive cells (MDSCs), resulting in downregulation of arginase 1 (Arg-1) and ROS to promote MDSCs apoptosis and reduce their immunosuppressive activity to CD8 + T cells. LIC-mediated immunogenic photodynamic therapy synergizes with MDSCstargeting immunotherapy, which significantly inhibits tumor growth via facilitating the dendritic cell maturation and tumor infiltration of CD8 + T cells while decreasing the tumor infiltration of immunosuppressive regulatory T cells, MDSCs, and M2-like tumor-associated macrophages. Moreover, the synergistic therapy increases the number of effector memory T cells (T EM ) in spleen, which suggests a favorable immune memory to prevent tumor recurrence and metastasis. The Ce6 and IPI-549-coloaded multifunctional nanodrug demonstrates high efficacy in colon cancer treatment.

BackgroundColon cancer has always been diagnosed at a late stage, which is associated with poor prognosis. The currently used serum tumor markers CEA and CA19-9 display low sensitivity and specificity and may not have diagnostic value in early stage colon cancer. Thus, there is an urgent need to identify novel serum biomarkers for use in the early detection of colon cancer.MethodsIn this study, the expression of DC-SIGN and DC-SIGNR in serum was detected by enzyme-linked immunosorbent assay (ELISA). DC-SIGN and DC-SIGNR expression was detected in cancer tissues by immunohistochemistry (IHC).ResultsThe level of sDC-SIGN was lower in patients than in the healthy controls, while the level of sDC-SIGNR in patients was higher than in the healthy controls. Both sDC-SIGN and sDC-SIGNR had diagnostic significances for cancer patients, and the combined diagnosis of these two markers was higher than both of them alone. Furthermore, there were significant differences between both sDC-SIGN and sDC-SIGNR in stage I/II patients and the healthy controls. Moreover, high sDC-SIGN level was accompanied with the long survival time. Additionally, DC-SIGNR was negative in the cancer foci and matched normal colon tissues but was weakly positive between the cancer foci. DC-SIGN staining was faint in matched normal colon tissues, strong in the tumor stroma and the invasive margin of colon cancer tissues, and negatively correlated with the sDC-SIGN level in serum from the same patient. Interestingly, the percent survival of patients with a DC-SIGN mean density of>0.001219 (the upper 95% confidence interval of matched normal colon tissues) was higher than for all other patients.ConclusionDC-SIGN and DC-SIGNR are blood-based molecular markers that can potentially be used for the diagnosis of early stage patients. Moreover, expression of DC-SIGN in serum and cancer tissues may affect the survival time for colon cancer patients.

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The aim of present study was to investigate the clinical significances of mannose receptor (MR) and CD163 in colorectal cancer (CRC). Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were utilized for this analysis. Preoperative serum MR and CD163 levels ranged from 0.153 to 0.804 μg/ml (median = 0.359 μg/ml) and from 0.319 to 1.314 μg/ml (median = 0.685 μg/ml) in CRC patients respectively. Strikingly, preoperative serum levels of MR and CD163 were significantly increased in CRC patients than in healthy individuals (P< 0.0001). ROC analyses suggested that the optimum diagnostic cut-offs for serum MR and CD163 were 0.3485 μg/ml (AUC 0.7205, sensitivity 54.82%, and specificity 80.46%) and 0.6111 μg/ml (AUC 0.7463, sensitivity 62.65%, and specificity 80.46%) respectively. Detection of serum MR and CD163 together obviously enhanced the diagnostic accuracy (AUC 0.7968, sensitivity 69.28%, and specificity 77.01%). Then, preoperative serum MR and CD163 levels correlated significantly with serum CEA, CA19-9 and CA72-4 concentrations in CRC patients (P< 0.05). High MR and CD163 expression in serum was associated significantly with shorter overall survival (P< 0.05) and demonstrated as adversely prognostic factors (P< 0.05). Further, expression of MR and CD163 in CRC tissues was significantly higher than that in para-cancer tissues (P< 0.001). High expression of MR and CD163 in CRC tissues also correlated significantly with shorter overall survival (P< 0.05). MR and CD163 expression in serum or CRC tissues all correlated positively with the degree of lymphatic metastasis (P< 0.0001). In conclusion, MR and CD163 may be novel biomarkers for CRC patients.

Soluble mannose receptor (sMR) and soluble haemoglobin scavenger receptor (sCD163) are macrophage activation markers which have previously been demonstrated to be increased in patients with inflammation, auto-immunity and malignancies. To investigate the clinical diagnostic and prognostic significance of preoperative serum sMR and sCD163, the present study investigated 143 gastric cancer (GC) patients, 66 subjects with benign gastric disease and 59 healthy controls, using an ELISA assay. Preoperative serum levels of sMR and sCD163 ranged from 0.165 to 0.885 µg/ml (median=0.374 µg/ml) and from 0.291 to 1.760 µg/ml (median=0.628 µg/ml) in GC patients, respectively. The expression levels of sMR and sCD163 were elevated compared with all controls (P<0.0001). Receiver operating characteristic analyses suggested that the optimum diagnostic cut-offs for sMR and sCD163 were 0.3405 µg/ml [area under curve (AUC) 0.7284, sensitivity 61.54%, and specificity 73.60%] and 0.6645 µg/ml (AUC 0.7766, sensitivity 53.85%, and specificity 86.40%), respectively. Notably, the measurement of serum sMR and sCD163 levels in conjugation, markedly enhanced the diagnostic accuracy (AUC 0.8490, sensitivity 70.63% and specificity 84.00%). Preoperative serum sMR and sCD163 levels correlated significantly with serum carcinoembryonic antigen, CA199, CA724 and CA125 concentrations in GC patients (P<0.05), however this association was not observed with sMR and CA724. High preoperative serum sMR and sCD163 levels correlated significantly with shorter overall survival (P=0.0041; P<0.0001, respectively) and were demonstrated to act as adverse prognostic factors (P=0.006; P<0.001, respectively). Furthermore, preoperative serum sMR and sCD163 levels correlated positively with the degree of lymphatic and distant metastasis of GC. In conclusion, preoperative serum sMR and sCD163 may be novel diagnostic and prognostic markers for GC and further studies are required in order to elucidate the underlying molecular mechanisms of sMR and CD163 in the development and progression of GC.