Dual depletion of myeloid-derived suppressor cells and tumor cells with self-assembled gemcitabine-celecoxib nano-twin drug for cancer chemoimmunotherapy.

Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.

Microarray Profile of Circular RNAs Identifies hsa_circ_0001583 as A New Circular RNA Biomarker for Breast Cancer: A Retrospective Study.

OBJECTIVE: Breast cancer (BC) is the most common cancer, which is currently the leading cause of cancer death. Circular RNAs (circRNAs) play important roles in cancer, however, circRNAs serving as vital index in BC for guiding treatment have not yet been identified. The aim of our study is to explore a novel kind of potential biomarker for BC. MATERIALS AND METHODS: In this retrospective study, the samples used for assays were two groups of breast tumor tissue obtained from four BC patients, including four pairs of tumor tissues and adjacent nontumor samples. The circRNA expression profiles were detected via microarray and validated by real-time quantitative polymerase chain reaction (PCR). RESULTS: The differentially expressed circRNAs in tested samples were screened and analyzed by using human circRNA microarray. After analysis, considering a fold gene expression change of ≥2.0 and P<0.05, results suggested that 256 circRNAs were significantly up-regulated and 277 circRNAs were significantly down-regulated. Besides, the results of the real-time quantitative PCR assay showed that the expression of hsa_circ_0001583 was significantly up-regulated in BC groups (P<0.05) by real-time quantitative PCR. Therefore, we thought hsa_circ_0001583 might serve as a novel kind of biomarker for BC. CONCLUSION: Hsa_circ_0001583 showed significant up-regulation in BC patients with paired adjacent tissues. Many cancer immune pathways were related to has_circ_0001583, including autoimmune thyroid disease, chemokine and T-cell receptor signaling pathways.

Crizotinib prodrug micelles co-delivered doxorubicin for synergistic immunogenic cell death induction on breast cancer chemo-immunotherapy.

Chemotherapeutic agents can trigger the immune response via inducing immunogenic cell death (ICD), but the weak ICD effect induced by chemotherapy alone limits its lasting antitumor immunotherapy effect. A Cro polymerized prodrug carriers (POEG-b-PCro) with immunostimulatory by ICD induction was developed and co-delivered DOX to generate synergistic ICD induction for chemo-immunotherapy on breast cancer. DOX/POEG-b-PCro micelles displayed prolonged circulation in blood, efficient accumulation in tumors, internalization and then co-released DOX&Cro in tumor cells. Moreover, the DOX/POEG-b-PCro micelles synergistically triggered ICD induction by releasing the nuclear high mobility group box 1 (HMGB1) and down-regulation of c-Met level for generating chemo-immune anti-tumor actions. Importantly, the DOX/POEG-b-PCro micelles synergistically enhanced the tumor cytotoxic T lymphocytes infiltration, concomitant decreasing the immunosuppressive regulatory T (Treg) cells, accompanied with the increased cytokines secretion of IFN-γ and TNF-α, consequently displaying an improved anti-tumor activity in 4 T1 breast cancer mice. Overall, POEG-b-PCro prodrug micelles co-delivered DOX could be served as a promising nano drug delivery system for synergistic ICD induction on breast cancer chemo-immunotherapy.