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.

Cancer Stem Cells in Ovarian Cancer—A Source of Tumor Success and a Challenging Target for Novel Therapies

“…Cancer stem cells have created mechanisms which enable them to escape from the host immune surveillance. In several human cancers, tumor-initiating cells equated to CSCs are able to reduce both the expression of human leukocyte antigens (HLA)—A, B and C—and antigen-processing machinery (APM) molecules, thus avoiding recognition by CD8+ cytotoxic T cells [ 358 , 359 , 360 , 361 , 362 ]. Cancer stem cells are also able to escape NK cell-mediated killing by the down-regulation of activating natural killer group 2D (NKG2D) ligands [ 358 , 360 , 363 ].…”

“…In several human cancers, tumor-initiating cells equated to CSCs are able to reduce both the expression of human leukocyte antigens (HLA)—A, B and C—and antigen-processing machinery (APM) molecules, thus avoiding recognition by CD8+ cytotoxic T cells [ 358 , 359 , 360 , 361 , 362 ]. Cancer stem cells are also able to escape NK cell-mediated killing by the down-regulation of activating natural killer group 2D (NKG2D) ligands [ 358 , 360 , 363 ]. Additionally, CSCs express low levels or no ligands for the NK cell activator receptors NKp44, NKp30, NKp46 and CD16 [ 364 , 365 , 366 ].…”

Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities

“…In this context, CSCs express a plethora of tumor-associated antigens (TAAs) on their surface, and most of them are still under intense investigation. Therapeutic strategies targeting some of these TAAs on CSCs can be promising approaches to overcome CSC-dependent drug resistance and tumor recurrence [15].…”

Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy

“…However, the genetic and cellular heterogeneity of the surrounding tumor microenvironment (TME) complicated the clinical efficacy of those treatments, which requires further understanding of the multiple aspects of tumor biology [ 4 ]. Along with the genetic and epigenetic instabilities, the nongenetic intra-tumor heterogeneity and plasticity conduct therapy failure due to the presence of the rare population of cancerous cells known as cancer stem cells (CSCs) or cancer-initiating cells (CICs) [ 5 , 6 ]. The self-renewal abilities of CSCs and the reversible differentiation of non-CSCs into CSCs all indicate their malignant characteristics to be actors of tumor recurrence, metastasis, and resistance to existing therapies [ 6 ].…”

“…The self-renewal abilities of CSCs and the reversible differentiation of non-CSCs into CSCs all indicate their malignant characteristics to be actors of tumor recurrence, metastasis, and resistance to existing therapies [ 6 ]. CSCs/CICs are identified by dynamic states of metabolome and cellular differentiation [ 7 ], their surface proteins (e.g., CD24, CD133, CD44, and LGR5), and intracellular molecular signature including aldehyde dehydrogenases (ALDHs) activity, overactivation of drug carriers (i.e., ABC transporters), and signaling pathways (e.g., Hedgehog, Notch, Wnt/β-catenin) [ 5 , 6 ]. The protected niche of CSCs is provided by overactivation of anti-apoptotic effectors, entering in dormancy state, activating autophagy during metabolic stress, and enhancing DNA damage response (DDR) to drugs targeting DNA synthesis or structure [ 6 ].…”