Targeting Cancer Stem Cells by Genetically Engineered Chimeric Antigen Receptor T Cells.

Rowa Y Alhabbab

doi:10.3389/fgene.2020.00312

Abstract

The term cancer stem cell (CSC) starts 25 years ago with the evidence that CSC is a subpopulation of tumor cells that have renewal ability and can differentiate into several distinct linages. Therefore, CSCs play crucial role in the initiation and the maintenance of cancer. Moreover, it has been proposed throughout several studies that CSCs are behind the failure of the conventional chemo-/radiotherapy as well as cancer recurrence due to their ability to resist the therapy and their ability to re-regenerate. Thus, the need for targeted therapy to eliminate CSCs is crucial; for that reason, chimeric antigen receptor (CAR) T cells has currently been in use with high rate of success in leukemia and, to some degree, in patients with solid tumors. This review outlines the most common CSC populations and their common markers, in particular CD133, CD90, EpCAM, CD44, ALDH, and EGFRVIII, the interaction between CSCs and the immune system, CAR T cell genetic engineering and signaling, CAR T cells in targeting CSCs, and the barriers in using CAR T cells as immunotherapy to treat solid cancers.

Highlights

Cancer stem cells (CSCs) were initially identified in acute myeloid leukemia (AML) and subsequently in several solid tumors such as breast, brain, gastric, and prostate tumors (Lapidot et al, 1994; Bonnet and Dick, 1997; Al-Hajj et al, 2003; Hemmati et al, 2003; Collins et al, 2005; Fukuda et al, 2009; Gupta et al, 2009)
CSCs are major obstacles in tumor treatment because even with the high effectiveness seen with the current chemo-/radiotherapy to remove most of the cancer cells, cancer patients usually suffer from relapse and cancer recurrence due to CSCs resistance, renewal, and differentiation ability initiating new tumor in treated patients (Reya et al, 2001; Hong et al, 2015; Kaiser, 2015; Kaur G. et al, 2018)
As this review mainly focuses on chimeric antigen receptor (CAR) T cells in targeting CSCs, the following sections discussed CAR T cells in details

Summary

INTRODUCTION

Cancer stem cells (CSCs) were initially identified in acute myeloid leukemia (AML) and subsequently in several solid tumors such as breast, brain, gastric, and prostate tumors (Lapidot et al, 1994; Bonnet and Dick, 1997; Al-Hajj et al, 2003; Hemmati et al, 2003; Collins et al, 2005; Fukuda et al, 2009; Gupta et al, 2009). CD44 is another common marker to identify CSCs in various cancer types, similar to CD133 and EpCAM It is transmembrane glycoprotein, it has several functions such as a receptor for hyaluronic acid, as well as the ability to be involve in the adhesion, migration, proliferation. CD133 accuracy as a phenotypic marker for CSC is still controversial, in which several studies found that CD133+ tissues are capable of regenerating tumor population with heterogenic properties in vitro and in vivo, whereas others reported that GBM cells expressing CD133 and CD133− cells have equal potential to generate tumor when transferred into nude mice (Singh et al, 2003, 2004; Beier et al, 2007). NK cells at this stage of development were characterized by their reduced cytotoxic ability upon interaction with CSCs, while interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) production is maintained, a functional state

Altering surface molecules expression

Secretion of anti-inflammatory molecules

Results obtained clinically

CONCLUSION