Previous reports have suggested that many gut microbiomes were associated with the development of colorectal cancer (CRC), and could modulate response to numerous forms of cancer therapy, including checkpoint blockade immunotherapy. Here we evaluated the protective efficacy of Lactobacillus acidophilus (L. acidophilus) cell lysates combined with an anti-CTL antigen-4 blocking antibody (CTLA-4 mAb) in syngeneic BALB/c mice CRC models induce by a single intraperitoneal injection of 10 mg/kg azoxymethane (AOM), followed by three cycles of 2% dextran sulfate sodium (DSS) in drinking water. In contrast to CTLA-4 mAb monotherapy, L. acidophilus lysates could attenuate the loss of body weight and the combined administration significantly protected mice against CRC development, which suggested that the lysates enhanced antitumor activity of CTLA-4 mAb in model mice. The enhanced efficacy was associated with the increased CD8 + T cell, increased effector memory T cells (CD44 + CD8 + CD62L+), decreased Treg (CD4 + CD25 + Foxp3+) and M2 macrophages (F4/80 + CD206+) in the tumor microenvironment. In addition, our results revealed that L. acidophilus lysates had an immunomodulatory effect through inhibition the M2 polarization and the IL-10 expressed levels of LPS-activated Raw264.7 macrophages. Finally, the 16S rRNA gene sequencing of fecal microbiota demonstrated that the combined administration significantly inhibited the abnormal increase in the relative abundance of proteobacteria and partly counterbalance CRC-induced dysbiosis in model mice. Overall, these data support promising clinical possibilities of L. acidophilus lysates with CTLA-4 mAb in cancer patients and the hypothesis that probiotics help shape the anticancer immune response.
Background and purpose: To evade immune defense, cancer cells can employ extracellular vesicles (EVs) to inhibit the anti-tumor activity of lymphocytes in the tumor microenvironment. However, the mechanisms and key molecules that mediate the effects of EVs on lymphocytes are unclear. Patients and methods: We used Quantibody ® Human Cytokine Antibody Array 440 to determine the tumor immunity-related cytokine profile of peripheral blood lymphocytes (PBLs) stimulated with EVs derived from peritoneal washes or malignant ascites. We detected 21 upregulated and 27 downregulated proteins, including the immunosuppressive receptors Siglec-10, SLAM, PD-1, and TIM-3. Results: Flow cytometry analysis of PBLs or ovarian cancer ascites suggested that Siglec-10 expression on CD3+ T cells was higher in ovarian cancer patients than in healthy controls and in the malignant ascites of ovarian cancer patients than in their blood. Moreover, the expression of CD24, the Siglec-10 ligand, was associated with tumor stage and cancer cell metastasis. Finally, compared to the benign peritoneal wash-derived EVs, the malignant EVs significantly upregulated Siglec-10 expression on Jurkat T cells, inhibited the protein kinase C activity induced by phorbol 12-myristate 13-acetate and ionomycin, and impaired the phosphorylation of the tyrosine kinase ZAP-70 activated by crosslinking with an anti-CD3 antibody. Conclusion: The EVs secreted by malignant ovarian cells upregulated Siglec-10 expression on T cells and impaired T cell activation in the tumor microenvironment. We believe that a comprehensive understanding of the regulation of Siglec-10 and CD24 by malignant EVs has clinical importance, as it will aid in the development of better immunotherapeutic strategies for ovarian cancer.
Endothelial protein C receptor (EPCR) has been implicated in the carcinogenesis of diverse tumor types. This tumor-promoting effect of EPCR is associated with the upregulation of activated protein C and the activation of protease-activated receptor 1 (PAR-1). However, the exact role of EPCR in gastric cancer (GC) and the mechanisms underlying the regulation of EPCR remain elusive. In the present study, we investigated the effects of EPCR on human GC cells, as well as the underlying mechanisms. An siRNA inference system was used to knock down the expression of EPCR in GC cells, and CCK-8, colony formation and Transwell assays were performed to determine the effects of EPCR knockdown on the proliferation and migration of the tumor cells. Additionally, cell cycle distribution and apoptosis were assessed by flow cytometry, and activated PAR-1 levels were determined by cell ELISA. The results indicated that the proliferation, clonogenicity and migration were significantly reduced and that the cell cycle was arrested in the Gap 1 phase by EPCR knockdown in SGC7901 and AGS cells. Meanwhile, apoptosis was promoted by EPCR knockdown in the two cell lines. The activation of PAR-1 on the cell surface of SGC7901 and AGS cells was significantly reduced after the knockdown of EPCR. By contrast, blockade of PAR-1 reduced the proliferation and migration of gastric cells in vitro. Additionally, after the knockdown of EPCR or treatment with PAR-1 antibody, the expression of pERK1/2 was significantly downregulated in the SGC7901 and AGS cells, while the expression levels of p-AKT (S473) and p-AKT (T308) were unchanged. The findings of the present study demonstrated that EPCR exerts pro-carcinogenic effects in GC cells in a PAR-1-dependent manner via the ERK1/2-MAPK pathway. Thus, EPCR may be a potential molecular diagnostic or therapeutic target for GC.
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