exhibited a preclinical efficacy of an mRNA-based DC vaccine using patient-derived breast cancer cells

exhibited a preclinical efficacy of an mRNA-based DC vaccine using patient-derived breast cancer cells. attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is (S)-3,5-DHPG associated with significant difficulties because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is usually opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/-catenin, noticeably fewer attempts were focused on the activation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic methods such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the security and efficacy of the different immunotherapeutic methods and describe the current state of their clinical development. Keywords: malignancy stem cells, CSC, bsAB, CAR-T cells, malignancy vaccines, immunotherapy 1. Introduction 1.1. CSC Definition and Clinical Significance Malignancy remains a leading cause of death worldwide, despite developments in its treatment [1]. Standard cancer treatments such as surgery, chemotherapy, and radiotherapy may be the most effective during an earlier stage of tumor development. However, treatment efficacy might be limited by tumor genetic and epigenetic heterogeneity. Each tumor is composed of cells with different features, including therapy resistance, metastatic dissemination, differentiation potential, and potency to maintain tumor growth [2]. Malignancy stem cells (CSC) are a populace of tumor Rabbit polyclonal to ETFDH cells that sustain tumor growth and heterogeneity [3]. CSCs were first characterized by Dick and colleagues for acute myeloid leukemia (AML) and proven to possess two fundamental properties, such as the capacity of self-renewal (e.g., an asymmetrical division that produces an identical copy and more differentiated progeny cells) and differentiation into multiple cellular subtypes observed within tumors [4,5,6]. Because of their self-renewal and differentiation capabilities, it has been shown that leukemia-initiating stem cells could repopulate and induce AML in severe combined immunodeficient hosts (SCID) after transplantation [3]. Different studies supported the tumor-initiating and tumor-maintaining properties of CSCs in various tumor entities [7,8,9]. CSCs have been characterized by many surface or intracellular markers in solid and hematological tumors. The most used indicators for CSC identification are surface markers such as CD133, CD44, and CD123, as well as the activity of some intracellular proteins such as aldehyde dehydrogenase (ALDH), as recently reviewed [10,11,12,13,14]. As the tumor evolves, the tumor microenvironment (TME) becomes progressively more crucial to maintaining the growth and functions of CSCs through the interplay with cellular components and modification of the extracellular matrix (ECM). The cellular components of TME, such as endothelial cells (ECs), mesenchymal cells (MSCs), immune cells, and cancer-associated fibroblasts (CAFs), play a role in therapeutic resistance by activating CSC-related signaling pathways such as Wnt, Notch, and nuclear factor kappa B (NF-B) pathways [15,16,17,18]. In turn, CSCs, by secreting several signaling factors, including pro-inflammatory cytokines and chemokines, recruit and alter the functions of stromal and immune cells to facilitate tumor growth and progression, especially during and after anticancer treatments, hence compromising treatment outcomes [19]. The exosomes released from CSCs can form the premetastatic niche via upregulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2), resulting in the activation of angiogenesis and promotion of metastatic growth [20]. Some CSCs can withstand conventional treatments such as chemo- and radiotherapy, which effectively destroys a large portion of the tumor bulk, causing tumor shrinkage. However, standard treatment often fails to prevent disease recurrence if the CSCs are not completely eradicated [21,22,23]. Some CSCs can resist the direct or indirect damages induced by ionizing irradiation. The explained mechanisms of the CSCs radioresistance include the activation of DNA damage response mechanisms (e.g., ATM, ATR, and (S)-3,5-DHPG Chk1/2), the scavenging of reactive oxygen species (ROS), protection from oxidative stress, activation (S)-3,5-DHPG of the anti-apoptotic pathways,.