Cancer cell targeting by CAR-T cells: A matter of stemness

Abstract

Chimeric antigen receptor (CAR)-T cell therapy represents one of the most innovative immunotherapy approaches. The encouraging results achieved by CAR-T cell therapy in hematological disorders paved the way for the employment of CAR engineered T cells in different types of solid tumors. This adoptive cell therapy represents a selective and efficacious approach to eradicate tumors through the recognition of tumor-associated antigens (TAAs). Binding of engineered CAR-T cells to TAAs provokes the release of several cytokines, granzyme, and perforin that ultimately lead to cancer cells elimination and patient's immune system boosting. Within the tumor mass a subpopulation of cancer cells, known as cancer stem cells (CSCs), plays a crucial role in drug resistance, tumor progression, and metastasis. CAR-T cell therapy has indeed been exploited to target CSCs specific antigens as an effective strategy for tumor heterogeneity disruption. Nevertheless, a barrier to the efficacy of CAR-T cell-based therapy is represented by the poor persistence of CAR-T cells into the hostile milieu of the CSCs niche, the development of resistance to single targeting antigen, changes in tumor and T cell metabolism, and the onset of severe adverse effects. CSCs resistance is corroborated by the presence of an immunosuppressive tumor microenvironment (TME), which includes stromal cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and immune cells. The relationship between TME components and CSCs dampens the efficacy of CAR-T cell therapy. To overcome this challenge, the double strategy based on the use of CAR-T cell therapy in combination with chemotherapy could be crucial to evade immunosuppressive TME. Here, we summarize challenges and limitations of CAR-T cell therapy targeting CSCs, with particular emphasis on the role of TME and T cell metabolic demands.

Keywords: CAR-T cell therapy; anti-cancer therapy; cancer stem cells; immunotherapy; tumor microenvironment.

FIGURE 1

Major mechanisms of anti-cancer therapy resistance of Cancer Stem Cells (CSCs). Schematic representation of the principal Cancer Stem Cells (CSCs) characteristics, including high expression of ABC drug efflux transporter, dormant status, metabolic plasticity, deregulation of tumor-associated antigens (TAAs), proficient DNA repair and escape of cell death mechanisms, which confer resistance to standard anti-cancer therapies.

FIGURE 2

Schematic representation of the immunosuppressive role of the tumor microenvironment (TME) on the CAR-T cell efficiency. Immunosuppressive tumor microenvironment (TME) including cancer-associated fibroblast (CAFs), M2-macrophages, myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg) negatively affect CAR-T cell activity against Cancer Stem Cells (CSCs). The development of CAR-T cell-based strategies against CSC-specific tumor associated antigens (TAAs), including EpCAM, CD44v6, CD166, c-Met, CD133, or against specific TME components antigens (A) including TR2, FRβ, SLAM-7 improve their functions.

FIGURE 3

Potential strategies to overcome CAR-T cell-based therapies limitations. Illustrative scheme of different strategies for cancer treatment showing four promising approaches, discussed throughout the manuscript. (1) CAR-T cell based therapies [EpCAM CAR-T (Deng et al., 2015), CD44v6 CAR-T (Casucci et al., 2013; Porcellini et al., 2020), CD166 CAR-T (Wang et al., 2019), c-Met CAR-T (Kang et al., 2021), CD133 CAR-T (Wang et al., 2018)]; (2) CAR-T cell based therapies plus conventional drugs [ROR1 CAR-T plus oxaliplatin (Srivastava et al., 2021), CD133 CAR-T plus cisplatin (Han Y. et al., 2021)]; (3) CAR-T cell based therapies plus monoclonal antibody [CD19 CAR-T plus tislelizumab (Wang et al., 2021), CD19 CAR-T plus avelumab or atezolizumab (Yamaguchi et al., 2022)]; and (4) CAR-T cell based therapies plus TKI inhibitors [PI3K inhibitor (Funk et al., 2022)]. All these alternative approaches are developed to improve the persistence of CAR-T cells and the improve immune response.