Cancer Stem Cells: Devil or Savior—Looking behind the Scenes of Immunotherapy Failure

Abstract

Although the introduction of immunotherapy has tremendously improved the prognosis of patients with metastatic cancers of different histological origins, some tumors fail to respond or develop resistance. Broadening the clinical efficacy of currently available immunotherapy strategies requires an improved understanding of the biological mechanisms underlying cancer immune escape. Globally, tumor cells evade immune attack using two main strategies: avoiding recognition by immune cells and instigating an immunosuppressive tumor microenvironment. Emerging data suggest that the clinical efficacy of chemotherapy or molecularly targeted therapy is related to the ability of these therapies to target cancer stem cells (CSCs). However, little is known about the role of CSCs in mediating tumor resistance to immunotherapy. Due to their immunomodulating features and plasticity, CSCs can be especially proficient at evading immune surveillance, thus potentially representing the most prominent malignant cell component implicated in primary or acquired resistance to immunotherapy. The identification of immunomodulatory properties of CSCs that include mechanisms that regulate their interactions with immune cells, such as bidirectional release of particular cytokines/chemokines, fusion of CSCs with fusogenic stromal cells, and cell-to-cell communication exerted by extracellular vesicles, may significantly improve the efficacy of current immunotherapy strategies. The purpose of this review is to discuss the current scientific evidence linking CSC biological, immunological, and epigenetic features to tumor resistance to immunotherapy.

Cancer stem cell antigens as targets for new combined anti-cancer therapies

“…The link between stemness and immunosuppression has been further confirmed by a TCGA analysis on 21 solid cancer types, and a negative association between stemness and interferon-/ signaling, and a striking positive association with several immunosuppressive genes, including TGFB1 and CD276 and CD155, two inhibitors of T and natural killer cells, were observed (21). Indeed, CSCs also inhibit immune effector cells thanks to the overexpression of several ICs, which, moreover, exert cell-intrinsic pro-tumoral mechanisms, favoring CSC survival and self-renewal (22). For instance, CSCs from melanoma, ovarian, colorectal and breast cancers express high levels of PD-L1 (23,24), which induces the AKT-dependent expression of the stem-cell markers OCT-4A, Nanog and BMI1 (25).…”

Cancer stem cells and macrophages: molecular connections and future perspectives against cancer

“…Immunoediting comprises all of the immune processes that lead to the control of tumor progression, including an important phase of immunosurveillance [ 134 ]. As a consequence of this tumor elimination phase, a specific subpopulation of CSCs is able to escape immune mechanisms to escape the immune response via, for example, the downregulation of antigen-presenting cells (APCs) [ 135 , 136 ]. As the presentation of tumor antigens from human leukocyte antigen (HLA)-1 to T cells is essential for the recognition phase, the expression of HLA-1 on CSCs may decrease as reported by Di Tomaso et al in a study on glioblastoma CSCs [ 137 ].…”

Extracellular Vesicles in the Tumour Microenvironment: Eclectic Supervisors

“…They drive neoplastic growth and recurrence, even after long latency. Moreover, CSC, due to their ability to modulate and shape immune responses, represent relevant mediators of resistance to immunotherapeutic approaches in cancer patients [28]. At this regard, it has been reported that renal 105 + CSC-EV drive immune-escape by targeting monocyte-derived DC [29].…”