Evidence of Antitumor and Antimetastatic Potential of Induced Pluripotent Stem Cell-Based Vaccines in Cancer Immunotherapy

Afag Asgarova,Jérôme Artus,Christophe Desterke,Frank Griscelli,Annelise Bennaceur-Griscelli,Ali G. Turhan,Diana Chaker,Masae Kishi

doi:10.3389/fmed.2021.729018

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.

Highlights

During the last decade, the concept of tumor heterogeneity has been extensively explored in solid tumors, leading to the identification, in several types of cancers, of dedifferentiated cancer cells, designated as “tumor-initiating cells” or “cancer stem cells” (CSCs) [1, 2]
Allogenic and Autologous induced pluripotent stem cells (iPSCs)-Based Cancer Vaccines well-known oncoprotein c-MYC, some of the key regulators of embryonic stem cells (ESCs), such as OCT4, SOX2, and NANOG, are abnormally over-expressed in CSCs of a broad range of malignancies [7, 8]. These three factors participate in a highly integrated network along with c-MYC and polycomb proteins that use the epigenetic machinery to remodel chromatin through histone modification and DNA methylation. This ability to induce major epigenetic modifications was first demonstrated by groundbreaking experiments leading to the discovery of induced pluripotent stem cell technology [9, 10]. iPSCs are closely linked to ESCs, as both express the same autoregulatory circuitries [11]
We evaluated for the first time the effects of a combinatory vaccination strategy using autologous and allogeneic iPS-whole cell-based vaccine along with a histone deacetylase inhibitor (HDACi) in cancer development in an aggressive murine breast carcinoma model with metastatic potential

Summary

Introduction

The concept of tumor heterogeneity has been extensively explored in solid tumors, leading to the identification, in several types of cancers, of dedifferentiated cancer cells, designated as “tumor-initiating cells” or “cancer stem cells” (CSCs) [1, 2]. Current evidence indicates that in addition to the Allogenic and Autologous iPSCs-Based Cancer Vaccines well-known oncoprotein c-MYC, some of the key regulators of embryonic stem cells (ESCs), such as OCT4, SOX2, and NANOG, are abnormally over-expressed in CSCs of a broad range of malignancies [7, 8]. These three factors participate in a highly integrated network along with c-MYC and polycomb proteins that use the epigenetic machinery to remodel chromatin through histone modification and DNA methylation. Subsequent analyses of the genomic characteristics of iPSCs revealed the occurrence of genetic abnormalities in iPSC arising either from the initial somatic parental cell [12, 13] or during their expansion in vitro [12]

Methods

Results

Conclusion