| Cancer is the deadliest disease worldwide, posing a great threat to public health. Immunotherapy against cancer have emerged as a promising alternative to conventional surgical intervention, radiotherapy, and chemotherapy. Numerous strategies exhibited meaningful benefits including antigen-based vaccines, adoptive cell therapy, checkpoint blockade and cytokines treatment. Unfortunately, its therapeutic benefits failed to live up to the expectations in a clinical setting. One mechanism postulated is that the tumors become less immunogenic and more capable to escape the immune detection. In addition, the treatment failure can be attributed to the activation of a plethora of inhibitory factors in the tolerant microenvironment, for example, a number of immunosuppressive cells, including regulatory T lymphocytes(Tregs). Recently, substantial evidence pointed out that chemotherapy could potentiate the anti-tumor efficiency of immunotherapy through multiple mechanisms. As far as we know, IL-2, a pleiotropic cytokine which play a critical role in the proliferation and activation of tumor-infiltrating lymphocytes(TILs), had been approved by the FDA to treat renal cancer and metastatic melanoma. Unfortunately, its clinical efficacy is partially hampered due to the immunosupression mediated by Tregs and myeloid-derived suppressor cells(MDSCs) within tumor microenvironment. In addition, as a bioactive agent, it can easily lose its biological activity because the delicate structure is not up against enzymatic degradation. In addition, systemic delivery of IL-2 could result in toxic side effects due to its rapid clearance in the circle. Recent data showed paclitaxel(PTX) selectively induced apoptosis of Tregs rather than effector T cells(Teff) via upregulation of the cell death receptor Fas. In addition, cytotoxic agents including PTX, can enhanced tumor cells immunogenicity, thereby promoting tumor antigens presentation to DCs to prime robust immune responses. However, because of the different physiochemical properties of PTX, a small hydrophobic drug, and IL-2, a soluble protein, co-encapsulation for sustained release of both agents posed a significant challenge for conventional carriers. Here, we developed a novel chemoimmunotherapy stragety via a thermoresponsive nanocarrier(TSN) which co-encapsulated low-dose paclitaxel(PTX), serving as enhancer of tumor cells immunogenicity as well as inhibition factor of regulatory T lymphocytes(Tregs), and immunostimulant interleukin-2(IL-2) as an activating factor of T lymphocytes and natural killer cells. The thermoresponsive platform, wherein a hydrophobic poly-lactic-glycolic-acid(PLGA) core is encapsulated within a hydrophilic sponge pluronic F127 shell with a surface polyethylene glycol(PEG) stretching out, enabled sustained and simultaneous release of encapsulants and promoted favourable pharmacokinetics and biodistribution. After injecting the formulation into mice intravenously, we evaluated its treatment benefits in both B16 melanoma subcutaneous tumor and lung metastatic tumor models. Results revealed that combined chemo-immunotherapy can significantly reduce tumor growth, inhibit metastasis and improve survival time than either immunotherapy or chemotherapy individually. Flow cytometry analysis on lymphocytes from tumor, lymph node and spleen indicated activation of adaptive and innate immune responses, particularly a bias of Th1 immune response in the tumor microenvironment. The synergistic mechanism attributed from the activation and engagement of both the tumor local immunity and systemic immunity response. Thus, pairing chemotherapy with immunotherapy could be potentially useful as effective treatment modality against cancer with the aid of the flexible platform in future. |
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