Inhibiting collagen I production and tumor cell colonization in the lung via miR-29a-3p loading of exosome-/liposome-based nanovesicles

The lung is one of the most common sites for cancer metastasis. Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells. Therefore, down-regulating the production of collagens may contribute to the inhibition of lung metastasis. It has been suggested that miR-29 exhibits effective anti-fibrotic activity by negatively regulating the expression of collagens. Indeed, our clinical lung tumor data shows that miR-29a-3p expression negatively correlates with collagen I expression in lung tumors and positively correlates with patients' outcomes. However, suitable carriers need to be selected to deliver this therapeutic miRNA to the lungs. In this study, we found that the chemotherapy drug cisplatin facilitated miR-29a-3p accumulation in the exosomes of lung tumor cells, and this type of exosomes exhibited a specific lung-targeting effect and promising collagen down-regulation. To scale up the preparation and simplify the delivery system, we designed a lung-targeting liposomal nanovesicle (by adjusting the molar ratio of DOTAP/cholesterol-miRNAs to 4:1) to carry miR-29a-3p and mimic the exosomes. This liposomal nanovesicle delivery system significantly down-regulated collagen I secretion by lung fibroblasts in vivo, thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells.

Progress in targeting therapy of cancer metastasis by CCL21/CCR7 axis / 生物工程学报

Metastasis is the leading cause of mortality for cancer patients, and lymphatic metastasis is one of the main ways of tumor metastasis. The role of CCL21 and its receptor CCR7 in lymphatic metastasis has been increasingly concerned in recent years. CCR7 is mainly expressed by both dendritic cells and T cells for immune responses. CCL21, the chemokine ligand for CCR7, secreted from lymphatic endothelial cells binds CCR7 and recruits immune cells toward lymphatic vessels and lymphatic nodes. CCR7 expressed tumor cells can also metastasize to lymphatic system by the similar way as immune cells. Targeting CCL21/CCR7 axis to inhibit lymphatic metastasis but remain potent anti-tumor immune response has increasingly become a spot light of tumor immunotherapy. In this review, we summarize the role of CCL21/CCR7 axis in lymphatic metastasis, as well as preclinical trials and clinical trials in targeting CCL21/CCR7 axis for tumor metastasis therapy, hoping to accelerate the progress on tumor metastasis therapy by targeting CCL21/CCR7 axis.

TNFR-1 on tumor cells contributes to the sensitivity of fibrosarcoma to chemotherapy

Impaired tumor necrosis factor receptor-1 (TNFR-1) signaling has been found in some malignant tumors with poor prognosis. However, the exact role of TNFR-1 signaling in fibrosarcoma remains unclear. Here, we explored the question by comparing the growth of TNFR-1 deficient (Tnfr1 (-)) and TNFR-1 competent (Tnfr1 (+)) fibrosarcoma FB61 cells (FB61-m and FB61-R1) in mice. TNFR-1 expression on fibrosarcoma cells delayed their growth in vivo but not in vitro. Moreover, reduced FB61-R1 tumor growth was also obtained in TNFR-1 knockout mice. The mechanism relies mainly on the TNFR-1-mediated downregulation of vascular endothelial growth factor (VEGF) production by tumor cells. Importantly, treatment of FB61-m tumors with melphalan resulted in a short delay of tumor growth, followed by a quick remission. However, when FB61-R1 tumors were treated with melphalan, tumor growth was similarly delayed at first and then completely rejected. Our results reveal evidence for TNFR-1 on tumor cells as a prerequisite in chemotherapy for fibrosarcoma, and provide novel insight into the therapeutic approach against some types of tumors using TNFR-1 angonist.

Selective expansion and enhanced anti-tumor effect of antigen-specific CD4(+) T cells by retrovirus-mediated IL-15 expression

Mounting evidence has demonstrated that CD4(+) T cells play an important role in anti-tumor immune responses. Thus, adoptive transfer of these cells may have great potential for anti-cancer therapy. However, due to the difficulty to generate sufficient tumor-specific CD4(+) T cells, the use of CD4(+) T cells in tumor therapy is limited. It has been found that IL-15 transfection enhances the proliferation and anti-tumor activity of tumor-specific CD8(+) T cells, but the effect of IL-15 transfection on CD4(+) T cells remains unknown. Here, the effects of retrovirus-mediated IL-15 expression in Ova-specific CD4(+) T cells from Do11.10 mice were evaluated and it was discovered that IL-15 transfected CD4(+) T cells expressed both soluble and membrane-bound IL-15. Retrovirus-mediated IL-15 expression led to a selective expansion of antigen-specific CD4(+) T cells by inhibiting their apoptosis. In vivo IL-15 transfected CD4(+) T cells were more effective in suppressing tumor growth than control retroviral vector transfected ones. To ensure the safety of the method, the employment of thymidine kinase gene made it possible to eliminate these transgenic CD4(+) T cells following ganciclovir treatment. Together, we show that IL-15 transfection induced a selective expansion of antigen-specific CD4(+) T cells ex vivo and enhanced their tumor-suppression effects in vivo. This has an important significance for improving the efficacy of adoptive T cell therapy.

The significance and function of IFN-γ on the changes of peripheral blood platelet count during tumor-rejection induced by a low dose of melphalan in C57BL/6 mice / 细胞与分子免疫学杂志

AIM: To investigate the significance and function of IFN-γ on the changes of peripheral blood platelet count during tumor-rejection induced by a low dose of melphalan in C57BL/6 mice. METHODS: Mouse tumor rejection model induced by a single dose of melphalan was used in this experiment. Different gene-type tumor-bearing mice (IFN-γ~(+/-) and IFN-γ~(-/-)), which had the same genetic background of C57BL/6, were treated intraperitoneally with melphalan (7.5 mg/kg). Tumor size was observed and recorded every one to three days in these different gene-type mice subsequently. Blood samples were obtained from orbital venous sinus on different days before and after melphalan treatment, and then complete blood counts were performed. The function of IFN-γ on the efficacy of chemotherapy and the changes of blood platelet count in IFN-γ~(+/-) and IFN-γ~(-/-) mice after melphalan treatment was analyzed. RESULTS: There was no significant difference in tumor sizes and blood platelet count between IFN-γ~(-/-) and IFN-γ~(+/-) mice (P>0.05). On the first day after melphalan (7.5 mg/kg) treatment, there were no significant changes in tumor sizes between mice in these two groups (P>0.05). Tumors shrank a little in IFN-γ~(-/-) mice and then grew gradually. Tumors relapsed in 2 w after melphalan injection in all IFN-γ~(-/-) mice, while tumor volumes decreased progressively and tumor cured at last in IFN-γ~(+/-) mice. The number of blood PLT in IFN-γ~(+/-) mice increased to (1935±378)×10~9/L 6 h after melphalan treatment, significantly higher than before (P0.05); While it sustained in normal range in IFN-γ~(-/-) mice. There was no significant difference in blood platelet count between IFN-γ~(-/-) and IFN-γ~(+/-) mice. CONCLUSION: Peripheral blood platelet count increased on the first day after melphalan treatment and tumors cured in IFN-γ~(+/-) mice; While tumors relapsed and there is no increase in blood platelet count on the first day after melphalan treatment in IFN-γ~(-/-)mice. These data indicated that the increase of blood PLT count was related to the function of IFN-γ in tumor-bearing mice in vivo during tumor rejection induced by a low dose of melphalan.

Experimental Tumor Immunotherapy with TNF Gens Transduced Cells / 中国肿瘤生物治疗杂志

The tumor necrosis factor(TNF) secreted by gene modified tumor cells can lead to very effective tumor rejection. This effect of TNF on tumor growth is mediated mainly by the induction of an antitumor immune response. It requires a local and continuous presence of TNF at the tumor site. Tumor suppression induced by TNF is close dependent and a complete tumor eradication must not be accompanied by systemic toxic side effects. A complex pattern of tumor infiltrating cells has been observed in TNF producing tumors, consisting of macrophages, CD4+ and CD8~(+)T cells. For efficient tumor inhibition maccophages and CD8~(+)T cells are needed,whereas CD4~(+)T cells seem to be innocent bystander cells. TNF is also effective in T eell deficient mice, but in most cases for complete tumor elimination T ceils have to be present. Depending on the cell lines used or the levels of TNF secreted by transduced tumor cells, systemic toxicity of TNF has also been observed including cachexia or wasting of the experimental animals. In some cases, TNF gene transfected tumors did not show growth inhibition in vivo, but rather, their metastases were enhanced. Using TNF producing tumor cells as vaccine, no systemic protective immunity against a parental tumor cell challenge has been observed.