Gąbka-Buszek Agnieszka, Kwiatkowska-Borowczyk Eliza, Jankowski Jakub, Kozłowska Anna Karolina, Mackiewicz Andrzej
Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8, Rokietnicka Street, 60-806 Poznan, Poland.
Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15, Garbary Street, 61-866 Poznan, Poland.
Vaccines (Basel). 2020 Mar 26;8(2):147. doi: 10.3390/vaccines8020147.
Therapeutic cancer vaccines have elicited renewed interest due to the development of immune checkpoint inhibitors. The role of these vaccines is to induce specific effector cells for killing cancer cells. Cancer stem cells (CSCs) are responsible for tumor growth and progression. Accordingly, they are targets for various cancer therapies, including immunotherapy. Here, we demonstrate the effectiveness of melanoma vaccines composed of genetically modified tumor cells admixed with melanoma stem-like cells (MSC) or induced pluripotent stem cells (iPSCs). Two vaccines were constructed. The first vaccine contained cells derived from B16F10 melanospheres (SFs) with CSC characteristics. The second vaccine contained syngeneic murine induced pluripotent stem cells (miPSCs). iPSCs or SF cells were admixed with B16F10 cells, modified with the designer cytokine Hyper-IL6(H6) (B16/H6). Control mice received B16/H6 cells, B16F10 cells or PBS. Immunization with either vaccine significantly inhibited tumor growth and increased disease-free survival (DFS) and overall survival (OS) in C57BL/6 mice. Mice treated with the SF or iPSC vaccine demonstrated increased activation of the immune response in the vaccination site and tumor microenvironment compared to those treated with B16/H6, B16F10 or PBS. Higher infiltration of dendritic cells (DCs) monocytes, and natural killer (NK) cells; lower numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs); higher levels of the cytokines INFγ and IL-12 were observed with the novel vaccines than with the control treatments. In vitro restimulation of splenocytes derived from mice immunized with B16F10 cell, SF cell or miPSC lysates increased the proliferation of CD4+ T helper lymphocytes and secretion of cytokines. An increased serum titer of antibodies directed against B16F10 cells was found in mice immunized with the SF vaccine. The most effective DFS and OS extensions were reached with the miPSCs vaccine. The described results form the basis for a novel platform for the next generation of cancer vaccines composed of allogeneic cancer-specific cells modified with a molecular adjuvant gene and admixed with allogeneic miPSCs or SFs.
由于免疫检查点抑制剂的发展，治疗性癌症疫苗引起了新的关注。这些疫苗的作用是诱导特异性效应细胞来杀伤癌细胞。癌症干细胞（CSCs）负责肿瘤的生长和进展。因此，它们是包括免疫疗法在内的各种癌症治疗的靶点。在此，我们证明了由基因改造的肿瘤细胞与黑色素瘤干细胞样细胞（MSC）或诱导多能干细胞（iPSCs）混合组成的黑色素瘤疫苗的有效性。构建了两种疫苗。第一种疫苗包含具有CSC特征的源自B16F10黑色素球（SFs）的细胞。第二种疫苗包含同基因小鼠诱导多能干细胞（miPSCs）。iPSCs或SF细胞与B16F10细胞混合，用设计细胞因子Hyper-IL6（H6）进行修饰（B16/H6）。对照小鼠接受B16/H6细胞、B16F10细胞或PBS。用任何一种疫苗免疫均显著抑制C57BL/6小鼠的肿瘤生长，并提高无病生存期（DFS）和总生存期（OS）。与用B16/H6、B16F10或PBS处理的小鼠相比，用SF或iPSC疫苗处理的小鼠在接种部位和肿瘤微环境中表现出免疫反应的激活增加。观察到新型疫苗组的树突状细胞（DCs）、单核细胞和自然杀伤（NK）细胞浸润更高；髓源性抑制细胞（MDSCs）和调节性T细胞（Tregs）数量更低；细胞因子INFγ和IL-12水平更高。用B16F10细胞、SF细胞或miPSC裂解物免疫的小鼠脾细胞的体外再刺激增加了CD4 + T辅助淋巴细胞的增殖和细胞因子的分泌。在用SF疫苗免疫的小鼠中发现针对B16F10细胞的抗体血清滴度增加。miPSCs疫苗实现了最有效的DFS和OS延长。所描述的结果为下一代癌症疫苗的新型平台奠定了基础，该平台由用分子佐剂基因修饰并与同种异体miPSCs或SFs混合的同种异体癌症特异性细胞组成。
