Kishi and Asgarova et al. evaluated iPSC-based vaccines combined with histone deacetylase inhibitor Valproic Acid (VPA) in a metastatic mouse model. Implanted murine 4T1 breast tumors showed enrichment of stemness signatures observed in iPSCs, and treatment with VPA alone upregulated MHC-I, but didn’t affect tumor growth. Vaccination with irradiated iPSCs combined with VPA treatment increased the frequency of CD4+ T cells, CD8+ T cells, and B cells; decreased immunosuppressive CD4+CD25+Foxp3+ Tregs, Arg1+CD11b+Gr1+ pre-MDSCs, and Arg1+CD11b+Ly6+ MDSCs in the TME; suppressed tumor growth and metastasis; and prolonged survival.
Contributed by Shishir Pant
ABSTRACT: Cancer is maintained by the activity of a rare population of self-renewing "cancer stem cells" (CSCs), which are resistant to conventional therapies. CSCs over-express several proteins shared with induced pluripotent stem cells (iPSCs). We show here that allogenic or autologous murine iPSCs, combined with a histone deacetylase inhibitor (HDACi), are able to elicit major anti-tumor responses in a highly aggressive triple-negative breast cancer, as a relevant cancer stemness model. This immunotherapy strategy was effective in preventing tumor establishment and efficiently targeted CSCs by inducing extensive modifications of the tumor microenvironment. The anti-tumoral effect was correlated with the generation of CD4+, CD8+ T cells, and CD44+ CD62L- CCR7low CD127low T-effector memory cells, and the reduction of CD4+ CD25+FoxP3+ Tregs, Arg1(+) CD11b+ Gr1+, and Arg1(+) and CD11b+ Ly6+ myeloid-derived suppressor cell populations within the tumor. The anti-tumoral effect was associated with a reduction in metastatic dissemination and an improvement in the survival rate. These results demonstrate for the first time the clinical relevance of using an off-the-shelf allogeneic iPSC-based vaccine combined with an HDACi as a novel pan-cancer anti-cancer immunotherapy strategy against aggressive tumors harboring stemness features with high metastatic potential.
Author Info: (1) Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France. (2) Instit
Author Info: (1) Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France. (2) Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France. (3) Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France. Université Paris-Saclay, Faculté de Médecine, Kremlin Bicêtre, France. (4) Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France. (5) Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France. Université Paris-Saclay, Faculté de Médecine, Kremlin Bicêtre, France. (6) Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France. Université Paris-Saclay, Faculté de Médecine, Kremlin Bicêtre, France. APHP Paris-Saclay Service d'Hématologie, Hôpital Universitaire Paris Sud (AP-HP), Kremlin Bicêtre, France. (7) Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France. Université Paris-Saclay, Faculté de Médecine, Kremlin Bicêtre, France. APHP Paris-Saclay Service d'Hématologie, Hôpital Universitaire Paris Sud (AP-HP), Kremlin Bicêtre, France. (8) Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France. Département de Biologie Médicale et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France.
