Crosstalk between thyroid CSCs and immune cells: basic principles and clinical implications

Abstract

Thyroid cancer has become the most common endocrine malignancy. Although the majority of differentiated thyroid cancers have a favorable prognosis, advanced thyroid cancers, iodine-refractory thyroid cancers, and highly malignant undifferentiated carcinomas still face a serious challenge of poor prognosis and even death. Cancer stem cells are recognized as one of the central drivers of tumor evolution, recurrence and treatment resistance. A fresh viewpoint on the oncological aspects of thyroid cancer, including proliferation, invasion, recurrence, metastasis, and therapeutic resistance, has been made possible by the recent thorough understanding of the defining and developing features as well as the plasticity of thyroid cancer stem cells (TCSCs). The above characteristics of TCSCs are complicated and regulated by cell-intrinsic mechanisms (including activation of key stem signaling pathways, somatic cell dedifferentiation, etc.) and cell-extrinsic mechanisms. The complex communication between TCSCs and the infiltrating immune cell populations in the tumor microenvironment (TME) is a paradigm for cell-extrinsic regulators. This review introduces the current advances in the studies of TCSCs, including the origin of TCSCs, the intrinsic signaling pathways regulating the stemness of TCSCs, and emerging biomarkers; We further highlight the underlying principles of bidirectional crosstalk between TCSCs and immune cell populations driving thyroid cancer progression, recurrence, or metastasis, including the specific mechanisms by which immune cells maintain the stemness and other properties of TCSCs and how TCSCs reshape the immune microenvironmental landscape to create an immune evasive and pro-tumorigenic ecological niche. Finally, we outline promising strategies and challenges for targeting key programs in the TCSCs-immune cell crosstalk process to treat thyroid cancer.

Keywords: immune cells; immunotherapy; targeting cancer stem cells; thyroid cancer; thyroid cancer stem cells.

Figure 1

Schematic representation of the origins and key markers of tumor stem cells (TCSCs). TCSCs can arise from (A) stem cells/progenitor cells, (B) Cancer cells, and (C) Embryonic-like stem cells.

Figure 2

Signaling pathways in TCSCs. (A) Wnt/β-catenin signaling pathway. KDM1A demethylates APC2 and DKK1, triggers Wnt signaling, starts the transcription of downstream target genes, and raises expression of stemness marker proteins. GSK-LSD1 effectively blocked KDM1A’s demethylation, preventing the abnormal stimulation of the Wnt/β-catenin pathway. (B) Notch signaling pathway. The ligand attaches itself to the Notch extracellular receptor, releasing the Notch intracellular structural domain (NICD). This NICD enters the nucleus and interacts with the CSL to control the expression of target genes downstream. Crenigacestat efficiently prevents TCSCs-driven tumor growth in vivo by reducing aldehyde dehydrogenase activity and blocking the Notch1-cMYC signaling pathway, which prevents the development of tumor balls. (C) Hippo signaling pathway. The Hh ligand attaches to the extracellular structural domain of PTCH upon activation of Hh signaling, blocking the receptor and removing its inhibitory action on SMO. Gli proteins can be dephosphorylated and transformed into their active state when Sufu’s function is inhibited by Smo. Target genes (like Snail) are expressed more when activated Gli1 enters the nucleus. By inhibiting Gli1, GANT61 suppresses the Shh pathway, delaying the formation of tumors fueled by TCSCs. (D) JAK/STAT signaling pathway. The cytokines control target gene transcription by binding to membrane receptors, activating JAKs, and mediating STAT phosphorylation into the nucleus. Through their targeting of the JAK/STAT3 signaling pathway, curcumin and cucurbitacin suppressed the expression of stemness genes and the tumor-promoting potential of TCSCs. (E) PI3K/AKT-SOX2 signaling. Diallyl trisulphide inhibited the tumorigenic ability of TCSCs by inhibiting the PI3K/AKT pathway, reducing the phosphorylation level of AKT and downstream SOX2 expression.

Figure 3

TCSCs ecological niche. (A) immune microenvironment. Through paracrine signaling or direct cell-to-cell contact, TCSCs communicate with immune cell cells in a variety of complex ways. This interaction influences the TME immune landscape’s formation and evolution and, to some extent, shapes the TCSCs’ capacity for self-renewal and multidirectional differentiation. (B) hypoxic microenvironment. Rapid tumor growth, pathologic angiogenesis, and stromal fibrosis all contribute to the TC’s inadequate oxygen supply in some areas. HIF-1α mediates hypoxia to suppress anti-tumor immunity and enhance the dryness of cancer cells, promoting the stem cell-like properties of thyroid cancer. (C) metabolic microenvironment. Through metabolic reprogramming, TCSCs effectively use scarce nutritional resources, such as glucose and glutamine, to satisfy the need for fast multiplication. However, the metabolic wastes they generate, including lactate and ROS, can also impair immune cell function. (D) acidic microenvironment. TCSCs accelerate the advancement of TC by increasing the production of lactic acid and the glycolytic pathway. This, in conjunction with protons and carbonic acid, creates an acidic milieu that supports TCSCs survival and impair immune cell function and provide an immunosuppressive environment that promotes the growth of tumors.

Figure 4

Crosstalk pathways between TCSCs and immune cells. (A) soluble molecules Both TCSCs and immune cells can release soluble molecules that facilitate information exchange and control one another’s reactions and behaviors, creating a dynamic web of interactions. (B) Metabolite Metabolites between TCSCs and immune cells can change each other’s phenotypic and functional states, further controlling their interactions. (C) EVs Immune cells and TCSCs can both release exosomes, which are microscopic vesicles that carry particular proteins and genetic information that are transferred from one cell to another to facilitate information sharing and function regulation. (D) Immune checkpoint TCSCs and immune cells recognize each other through ligands and receptors, forming signaling pathways that regulate immune responses and shape the immune microenvironment.

Figure 5

Crosstalk between TCSCs and immune cells. (A) TCSCs release immunomodulatory substances (CCL2, CCL15, and CSF 1) and metabolites (e.g., lactate) that promote macrophage recruitment and M2-like TAM polarization. TCSCs can also avoid being phagocytosed by macrophages by expressing CD47. TAM secretes wnt1 and wnt3a, which promote TCSCs’ ability to proliferate. (B) TCSCs release SCF to attract c-kit-expressing MCs into the TME, while MCs emit TNF-α, IL-6, and IL-8 to support TCSCs’ self-renewal ability, stem cell markers, and the EMT process for TC invasion and development. (C) TCSCs evade recognition and attack by CD8 + T lymphocytes either through immune checkpoints (MHC-I and PD-L1) or by secreting SIGLEC15. The acetylcholine produced by nerves acts on TCSCs to up-regulate the expression of PD-L1 and further inhibits the function of CD8+ T cells by competing for nutrients and the accumulation of metabolites, thereby promoting the self-renewal and immune escape of TCSCs. (D) Metabolites from TCSCs serve as substrates to increase CAF’s TCA cycling activity, which effectively sustains TCSCs’ high energy flux absorption. By regulating the JAK/STAT3 and PI3K/Akt signaling pathways, CAF encourages the growth and invasiveness of TCSCs.

Figure 6

Therapeutic targeting of crosstalk between TCSCs and immune cells. Therapeutic strategies to target thyroid cancer stem cell and immune cell crosstalk may include the following: Targeting TCSCs, Immunotherapy, Combination therapy.