Exosomes from GM-CSF expressing embryonic stem cells are an effective prophylactic vaccine for cancer prevention

Abstract

The antigenic similarity between embryos and tumors has raised the idea of using embryonic material as a preventative vaccine against neoplastic disease. Indeed, we have previously reported that a vaccine comprises allogeneic murine embryonic stem cells (ESCs) and murine fibroblasts expressing GM-CSF (to amplify immune responses) successfully blocks the outgrowth of an implantable cancer (Lewis lung carcinoma; LLC) and lung tumors generated in mice using a combination of a mutagen followed by chronic pulmonary inflammation. However, such a vaccine is obviously impractical for application to humans. The use of fibroblasts to generate GM-CSF is needlessly complicated, and intact whole ESCs carry the hazard of generating embryomas/teratomas. Here, we report the successful application of an alternative prophylactic vaccine comprises exosomes derived from murine ESCs engineered to produce GM-CSF. Vaccination of mice with these exosomes significantly slowed or blocked the outgrowth of implanted LLC while control exosomes lacking GM-CSF were ineffective. Examination of tumor-infiltrating immune cells from mice vaccinated with the GM-CSF-expressing exosomes showed robust tumor-reactive CD8 + T effector responses, Th1 cytokine responses, and higher CD8 + T effector/CD4 + CD25 + Foxp3 + T regulatory cell ratio in the tumors. We conclude that a similar vaccine derived from GM-CSF-expressing human ESCs can be employed as a preventative vaccine for humans with an increased risk of developing cancer.

Exosomes and Extracellular Vesicles in Myeloid Neoplasia: The Multiple and Complex Roles Played by These “Magic Bullets”

“…Thus, exosomes from cultured cell media may represent an effective way to develop vaccines based on maturing DCs, even if recent data suggest that there is probably a synergic effect between vesicular and soluble molecules [157]. Considering the recent activation of anti-WT1 vaccine clinical trials for AMLs [158,159] and the results reported for antitumor vaccines [160], exosome-based vaccines are expected to be widely explored in the future, and the upcoming results would hopefully impact the way we manage AML cases.…”

Immunoregulatory Roles of Extracellular Vesicles and Associated Therapeutic Applications in Lung Cancer

“…Similarly, EVs derived from immune cells contain many functional molecules and mediate communication among immune cells ( 43 , 50 – 54 ). Additionally, EVs from embryonic stem cells also possess some antigens similar to those from cancer cells ( 31 ). All immunosuppressive and immunostimulatory cargo in EVs discussed in this review are listed in Tables 1 , 2 , respectively.…”

“…Common antigens between tumor and embryonic cells are the immunological basis for using embryonic cells as antitumor vaccines ( 98 ). An interesting attempt was conducted to stimulate antitumor immunity by using exosomes from ESCs, which may express similar carcinoembryonic antigens as some tumor cell types ( 31 ) ( Figure 3A ). Vaccination with exosomes from granulocyte-macrophage colony-stimulating factor (GM-CSF)–expressing murine embryonic stem cells could prevent the growth of implanted LLC lung adenocarcinoma, B16-F10 melanoma, MC-38 colon adenocarcinoma, and 4T1 mammary carcinoma but not E0771 medullary breast adenocarcinoma in allogeneic mice ( 31 ).…”

“…An interesting attempt was conducted to stimulate antitumor immunity by using exosomes from ESCs, which may express similar carcinoembryonic antigens as some tumor cell types ( 31 ) ( Figure 3A ). Vaccination with exosomes from granulocyte-macrophage colony-stimulating factor (GM-CSF)–expressing murine embryonic stem cells could prevent the growth of implanted LLC lung adenocarcinoma, B16-F10 melanoma, MC-38 colon adenocarcinoma, and 4T1 mammary carcinoma but not E0771 medullary breast adenocarcinoma in allogeneic mice ( 31 ). This vaccine resulted in increased tumor cell-specific CD8 + T-cells and a decreased percentage of MDSCs in the spleen and raised the ratio of CD8 + T-effector cells to Tregs in the tumor ( 31 ).…”

“…Vaccination with exosomes from granulocyte-macrophage colony-stimulating factor (GM-CSF)–expressing murine embryonic stem cells could prevent the growth of implanted LLC lung adenocarcinoma, B16-F10 melanoma, MC-38 colon adenocarcinoma, and 4T1 mammary carcinoma but not E0771 medullary breast adenocarcinoma in allogeneic mice ( 31 ). This vaccine resulted in increased tumor cell-specific CD8 + T-cells and a decreased percentage of MDSCs in the spleen and raised the ratio of CD8 + T-effector cells to Tregs in the tumor ( 31 ). This ESEV vaccine could avoid the risk of embryomas/teratomas caused by the whole-ESC vaccine.…”