The Immune Privilege of Cancer Stem Cells: A Key to Understanding Tumor Immune Escape and Therapy Failure

Abstract

Cancer stem cells (CSCs) are broadly considered immature, multipotent, tumorigenic cells within the tumor mass, endowed with the ability to self-renew and escape immune control. All these features contribute to place CSCs at the pinnacle of tumor aggressiveness and (immune) therapy resistance. The immune privileged status of CSCs is induced and preserved by various mechanisms that directly affect them (e.g., the downregulation of the major histocompatibility complex class I) and indirectly are induced in the host immune cells (e.g., activation of immune suppressive cells). Therefore, deeper insights into the immuno-biology of CSCs are essential in our pursuit to find new therapeutic opportunities that eradicate cancer (stem) cells. Here, we review and discuss the ability of CSCs to evade the innate and adaptive immune system, as we offer a view of the immunotherapeutic strategies adopted to potentiate and address specific subsets of (engineered) immune cells against CSCs.

Keywords: cancer stem cells; immune escape; immunogenicity; immunotherapy; tumor microenvironment.

Figure 1

Immune escape mechanisms of CSCs. Cancer stem cells (CSCs) adopt several tricks to escape immune control. First, CSCs avoid the recognition by CD8⁺ T cells by reducing the human leukocyte antigen-A, B, C (HLA-A, B, C) and the antigen processing machinery (APM) molecule expression. Second, CSCs impair the cytotoxicity of natural killer (NK) cells by downregulating the natural killer group 2D (NKG2D) ligand expression. Third, the ligation of immune checkpoint ligands such as programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), B7 homolog 3 (B7-H3) and B7 homolog 4 (B7-H4) expressed by CSCs to their respective receptors on T cells decreases their proliferation and interferon-γ (IFN-γ) production or leads to apoptosis. Fourth, CSCs upmodulate the “don’t eat me” signal CD47 that blocks their phagocytosis through the interaction with the membrane glycoprotein signal regulatory protein α (SIRP-α) expressed on the surface of macrophages (Mφs). Fifth, CSCs acquire a state of dormancy by entering into a G0 phase of cell cycle arrest. The cancer dormancy protects CSCs from immune control, ensuring their survival and eventually their metastatic dissemination.

Figure 2

Immunotherapeutic targeting of CSC antigens. Cancer stem cells (CSCs) express several tumor-associated antigens (TAAs). CSCs are selectively targeted by means of dendritic cells (DCs) and genetically modified T cells (T cell receptor (TCR) T cells and chimeric antigen receptor (CAR) T cells). DC-based vaccines consist of DC expansion and loading with CSC specific antigen to prime CD8⁺ T cells, which, in turn, recognize and eliminate CSCs. TCR-engineered T cells are T cells equipped with a genetically modified TCR that specifically recognizes tumor antigen presented by human leukocyte antigen-A, B, C (HLA-A, B, C) on the surface of CSCs. CAR-T cells are T cells engineered to express a CD3ζ intracellular domain joined to an antibody receptor that recognizes tumor antigens exposed on CSC surface in an HLA-unrestricted manner. Some TAAs, such as aldehyde dehydrogenase (ALDH), human telomerase (hTERT) and survivin, and a cancer testis, (CT) antigen such as premelanosome protein (PMEL), are under clinical trial.

Figure 3

CSC immunomodulatory patterns impairing innate and adaptive immune system. A schematic model showing the plethora of cellular, molecular and physical factors either released from cancer stem cells (CSCs) within the tumor microenvironment (TME) or exposed by their surface that create an immune contexture crowded with immunosuppressive cells such as M2 tumor associated macrophages (TAMs), myeloid derived suppressor cells (MDSCs) and T regulatory cells (Tregs) and impaired cytotoxic T lymphocytes (CTLs).