Detrimental activation of AhR pathway in cancer: an overview of therapeutic strategies.

Sustained transcriptional activation of the aryl hydrocarbon receptor (AhR) promotes tumour growth and impairs the immune defence, at least for cutaneous melanoma and glioma. AhR ligands are produced by the tumour microenvironment (TME) and by the tumour itself (intracrine). The recent identification of interleukin-4-induced-1 (IL4I1), a parallel pathway to indoleamine 2 3-dioxygenase 1 (IDO1)/ tryptophan 2,3-dioxygenase (TDO), and its ability to generate AhR ligands, confirms that a complete inhibition of AhR ligand production might be difficult to reach. Here, we have focused on recent discoveries explaining the large varieties of AhR ligands and the functional consequences in terms of cancer cell plasticity and consecutive therapy resistance. We also examined therapeutic strategies targeting the AhR signalling pathway and their possible adverse effects. Since the end of 2019, two phase I clinical trials have investigated the ability of the AhR antagonist to 'reset' the immune system and re-sensitize the cancer cells to therapies by preventing their dedifferentiation.

How Tumor Cell Dedifferentiation Drives Immune Evasion and Resistance to Immunotherapy.

Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. While tumor antigens are needed for effective immunotherapy, a favorable tumor immune microenvironment is also critical. In this review, we discuss emerging evidence that tumor cells exploit cellular plasticity and dedifferentiation programs to avoid immune surveillance, which in turn drives metastatic dissemination and resistance to immunotherapy. A deeper understanding of these programs may provide novel opportunities to enhance the efficacy of existing immunotherapies.

Overexpression of early T cell differentiation-specific transcription factors transforms the terminally differentiated effector T cells into less differentiated state.

The in vivo proliferation and viability of transfused engineered T cells markedly limits the long-term effect of adoptive cell therapy on tumors. The therapeutic efficacy and proliferative potential of T cells are reported to be dependent on the differentiation status of T cells. The T cells at the early stage of progressive differentiation have a long lifespan, strong proliferative potential, and the ability to reconstruct intact T cell subsets. Thus, they are more suitable for adoptive immunotherapy. Previously, it was difficult to obtain a sufficient number of early differentiated T cells by inhibiting the progressive differentiation of T cells or by two-step programming. A more effective strategy is to directly reprogram and dedifferentiate the easily available terminal effector T (TEFF) cells, which are generated in large numbers, into early T cells. This study attempted to overexpress eight (candidate) early differentiation-specific transcription factors (TFs) (LEF1, KLF7, ID3, EOMES, BCL6, TCF7, FOXP1, and FOXO1) in the TEFF cells, which were activated by in vitro stimulation, to promote dedifferentiation into early T cells. In the mature TEFF cells simultaneously overexpressing these specific TFs, the expression pattern of T cell differentiation markers (CCR7 and CD45RO) exhibited a tendency to change to the pattern observed during early differentiation. The transcriptome analysis revealed that the function of differentially expressed genes was mainly concentrated in the cell cycle, growth and development, and effector function. Moreover, many genes related to early differentiated T cells (such as BCL2 and PIM1) were significantly upregulated, while those related to the effector function of TEFF cells were significantly downregulated (such as GZMB, PRF1, and GNLY). Additionally, the TEFF cells overexpressing characteristic TFs exhibited enhanced anti-apoptotic capabilities and decreased secretion of cytokines (IFN-γ and TNF-α). Based on these results, we believe that the TEFF cells were reprogrammed into a less differentiated state after overexpression of the eight specific TFs.

Bidirectional Crosstalk Between Cancer Stem Cells and Immune Cell Subsets.

Cancer stem cells (CSCs), also known as tumor-initiating cells, are characterized by an increased capacity for self-renewal, multipotency, and tumor initiation. While CSCs represent only a small proportion of the tumor mass, they significantly account for metastatic dissemination and tumor recurrence, thus making them attractive targets for therapy. Due to their ability to sustain in dormancy, chemo- and radiotherapy often fail to eliminate cancer cells with stemness properties. Recent advances in the understanding of the tumor microenvironment (TME) illustrated the importance of the immune contexture, determining the response to therapy and clinical outcome of patients. In this context, CSCs exhibit special properties to escape the recognition by innate and adaptive immunity and shape the TME into an immunosuppressive, pro-tumorigenic landscape. As CSCs sculpt the immune contexture, the phenotype and functional properties of the tumor-infiltrating immune cells in turn influence the differentiation and phenotype of tumor cells. In this review, we summarize recent studies investigating main immunomodulatory properties of CSCs and their underlying molecular mechanisms as well as the impact of immune cells on cancer cells with stemness properties. A deeper understanding of this bidirectional crosstalk shaping the immunological landscape and determining therapeutic responses will facilitate the improvement of current treatment modalities and the design of innovative strategies to precisely target CSCs.

IL-22 produced by Th22 cells aggravates atherosclerosis development in ApoE-/- mice by enhancing DC-induced Th17 cell proliferation.

Th22 cells are a novel subset of CD4+ T cells that primarily mediate biological effects through IL-22, with both Th22 cells and IL-22 being closely associated with multiple autoimmune and chronic inflammatory diseases. In this study, we investigated whether and how Th22 cells affect atherosclerosis. ApoE-/- mice and age-matched C57BL/6J mice were fed a Western diet for 0, 4, 8 or 12 weeks. The results of dynamic analyses showed that Th22 cells, which secrete the majority of IL-22 among the known CD4+ cells, play a major role in atherosclerosis. ApoE-/- mice fed a Western diet for 12 weeks and administered recombinant mouse IL-22 (rIL-22) developed substantially larger plaques in both the aorta and aortic root and higher levels of CD3+ T cells, CD68+ macrophages, collagen, IL-6, Th17 cells, dendritic cells (DCs) and pSTAT3 but lower smooth muscle cell (SMC) α-actin expression than the control mice. Treatment with a neutralizing anti-IL-22 monoclonal antibody (IL-22 mAb) reversed the above effects. Bone marrow-derived DCs exhibited increased differentiation into mature DCs following rIL-22 and ox-LDL stimulation. IL-17 and pSTAT3 were up-regulated after stimulation with IL-22 and ox-LDL in cells cocultured with CD4+ T cells and mature DC supernatant, but this up-regulation was significantly inhibited by IL-6mAb or the cell-permeable STAT3 inhibitor S31-201. Thus, Th22 cell-derived IL-22 aggravates atherosclerosis development through a mechanism that is associated with IL-6/STAT3 activation, DC-induced Th17 cell proliferation and IL-22-stimulated SMC dedifferentiation into a synthetic phenotype.

Virus-like infection induces human ß cell dedifferentiation.

Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic ß cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than ß cell death, suggesting loss of ß cell identity. We undertook this study to examine whether viral infection could induce human ß cell dedifferentiation. Using the functional human ß cell line EndoC-ßH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in ß cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-κB pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-α. Lastly, we identified SOX9 targets in human ß cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human ß cell dedifferentiation.

MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment.

Inflammation promotes phenotypic plasticity in melanoma, a source of non-genetic heterogeneity, but the molecular framework is poorly understood. Here we use functional genomic approaches and identify a reciprocal antagonism between the melanocyte lineage transcription factor MITF and c-Jun, which interconnects inflammation-induced dedifferentiation with pro-inflammatory cytokine responsiveness of melanoma cells favouring myeloid cell recruitment. We show that pro-inflammatory cytokines such as TNF-α instigate gradual suppression of MITF expression through c-Jun. MITF itself binds to the c-Jun regulatory genomic region and its reduction increases c-Jun expression that in turn amplifies TNF-stimulated cytokine expression with further MITF suppression. This feed-forward mechanism turns poor peak-like transcriptional responses to TNF-α into progressive and persistent cytokine and chemokine induction. Consistently, inflammatory MITF(low)/c-Jun(high) syngeneic mouse melanomas recruit myeloid immune cells into the tumour microenvironment as recapitulated by their human counterparts. Our study suggests myeloid cell-directed therapies may be useful for MITF(low)/c-Jun(high) melanomas to counteract their growth-promoting and immunosuppressive functions.

GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow.

GATA2 plays a crucial role for the mast cell fate decision. We herein demonstrate that GATA2 is also required for the maintenance of the cellular identity in committed mast cells derived from mouse bone marrow (BMMCs). The deletion of the GATA2 DNA binding domain (GATA2ΔCF) in BMMCs resulted in a loss of the mast cell phenotype and an increase in the number of CD11b- and/or Ly6G/C-positive cells. These cells showed the ability to differentiate into macrophage- and neutrophil-like cells but not into eosinophils. Although the mRNA levels of basophil-specific genes were elevated, CD49b, a representative basophil marker, never appeared on these cells. GATA2 ablation led to a significant upregulation of C/EBPα, and forced expression of C/EBPα in wild-type BMMCs phenocopied the GATA2ΔCF cells. Interestingly, simultaneous deletion of the Gata2 and Cebpa genes in BMMCs restored the aberrant increases of CD11b and Ly6G/C while retaining the reduced c-Kit expression. Chromatin immunoprecipitation assays indicated that GATA2 directly binds to the +37-kb region of the Cebpa gene and thereby inhibits the RUNX1 and PU.1 binding to the neighboring region. Upregulation of C/EBPα following the loss of GATA2 was not observed in cultured mast cells derived from peritoneal fluid, whereas the repression of c-Kit and other mast cell-specific genes were observed in these cells. Collectively, these results indicate that GATA2 maintains cellular identity by preventing Cebpa gene activation in a subpopulation of mast cells, whereas it plays a fundamental role as a positive regulator of mast cell-specific genes throughout development of this cell lineage.

Effect of JJYMD-C, a novel synthetic derivative of gallic acid, on proliferation and phenotype maintenance in rabbit articular chondrocytes in vitro

Tissue engineering encapsulated cells such as chondrocytes in the carrier matrix have been widely used to repair cartilage defects. However, chondrocyte phenotype is easily lost when chondrocytes are expanded in vitro by a process defined as “dedifferentiation”. To ensure successful therapy, an effective pro-chondrogenic agent is necessary to overcome the obstacle of limited cell numbers in the restoration process, and dedifferentiation is a prerequisite. Gallic acid (GA) has been used in the treatment of arthritis, but its biocompatibility is inferior to that of other compounds. In this study, we modified GA by incorporating sulfamonomethoxine sodium and synthesized a sulfonamido-based gallate, JJYMD-C, and evaluated its effect on chondrocyte metabolism. Our results showed that JJYMD-C could effectively increase the levels of the collagen II, Sox9, and aggrecan genes, promote chondrocyte growth, and enhance secretion and synthesis of cartilage extracellular matrix. On the other hand, expression of the collagen I gene was effectively down-regulated, demonstrating inhibition of chondrocyte dedifferentiation by JJYMD-C. Hypertrophy, as a characteristic of chondrocyte ossification, was undetectable in the JJYMD-C groups. We used JJYMD-C at doses of 0.125, 0.25, and 0.5 µg/mL, and the strongest response was observed with 0.25 µg/mL. This study provides a basis for further studies on a novel agent in the treatment of articular cartilage defects.

Effect of JJYMD-C, a novel synthetic derivative of gallic acid, on proliferation and phenotype maintenance in rabbit articular chondrocytes in vitro.

Tissue engineering encapsulated cells such as chondrocytes in the carrier matrix have been widely used to repair cartilage defects. However, chondrocyte phenotype is easily lost when chondrocytes are expanded in vitro by a process defined as "dedifferentiation". To ensure successful therapy, an effective pro-chondrogenic agent is necessary to overcome the obstacle of limited cell numbers in the restoration process, and dedifferentiation is a prerequisite. Gallic acid (GA) has been used in the treatment of arthritis, but its biocompatibility is inferior to that of other compounds. In this study, we modified GA by incorporating sulfamonomethoxine sodium and synthesized a sulfonamido-based gallate, JJYMD-C, and evaluated its effect on chondrocyte metabolism. Our results showed that JJYMD-C could effectively increase the levels of the collagen II, Sox9, and aggrecan genes, promote chondrocyte growth, and enhance secretion and synthesis of cartilage extracellular matrix. On the other hand, expression of the collagen I gene was effectively down-regulated, demonstrating inhibition of chondrocyte dedifferentiation by JJYMD-C. Hypertrophy, as a characteristic of chondrocyte ossification, was undetectable in the JJYMD-C groups. We used JJYMD-C at doses of 0.125, 0.25, and 0.5 µg/mL, and the strongest response was observed with 0.25 µg/mL. This study provides a basis for further studies on a novel agent in the treatment of articular cartilage defects.

Innate immune response precedes Mycobacterium leprae-induced reprogramming of adult Schwann cells.

Recently, we showed a natural reprogramming process during infection with Mycobacterium leprae (ML), the causative organism of human leprosy. ML hijacks the notable plasticity of adult Schwann cells in the peripheral nervous system (PNS), bacteria's preferred nonimmune niche, to reprogram infected cells to progenitor/stem cell-like cells (pSLCs). Whereas ML appear to use this reprogramming process as a sophisticated bacterial strategy to spread infection to other tissues, understanding the mechanisms may shed new insights into the basic biology of cellular reprogramming and the development of new approaches for generating pSLC for therapeutic purposes as well as targeting bacterial infectious diseases at an early stage. Toward these goals, we extended our studies to identify other players that might be involved in this complex host cell reprogramming. Here we show that ML activates numerous immune-related genes mainly involved in innate immune responses and inflammation during early infection before downregulating Schwann cell lineage genes and reactivating developmental transcription factors. We validated these findings by demonstrating the ability of infected cells to secrete soluble immune factor proteins at early time points and their continued release during the course of reprogramming. By using time-lapse microscopy and a migration assay with reprogrammed Schwann cells (pSLCs) cultured with macrophages, we show that reprogrammed cells possess the ability to attract macrophages, providing evidence for a functional role of immune gene products during reprogramming. These findings suggest a potential role of innate immune response and the related signaling pathways in cellular reprogramming and the initiation of neuropathogenesis during ML infection.

The meaning of the anti-cancer antibody CLN-IgG (Pritumumab) generated by human × human hybridoma technology against the cyto-skeletal protein, vimentin, in the course of the treatment of malignancy.

Cancer stem cells in a tumor mass form a very small subpopulation ranging from below 0.1% in a brain tumor but they have the crucial ability to become malignant. The goal of cancer therapy has been the total killing of tumor cells. However we should clarify that most of all tumor cells are differentiated cancer cells. Thus the elimination of 99.9% of tumor cells under histological criteria cannot ensure the cancer will be cured. Rather cancer cell biologists should turn their attention to reprogramming cancer stem cells to normal stem cells by which malignancy recuperates normal organogenesis from the aspect of the dichotomy of cancer stem cell. The cue points underlying the reverse cancer stem cell at blastogenesis in inflammation site is depending upon cell-to-cell recognition of the tumor-niche cells. Normalization of tumor-niche promises to lead cancer stem cell into normal stem cell owing to autonomous healing mechanisms that reside in the self-defense mechanisms in immunity and the cell competition mechanisms in the wound healing of the tissue cells. Among the cyto-skeletal proteins, vimentin becomes a target of self-restoration of cancer stem cell by means of immune surveillance. A human monoclonal antibody, CLN-IgG recognizes vimentin expressing on the cell surface of the malignant tumor. Since vimentin network resides in the cytoplasm connecting the plasma membrane with chromatin assembly in the nucleus, it is highly likely vimentin plays an important role in up-regulation and down-regulation through signal transduction between certain membrane receptors and gene expression with respect to the transformation of the cell. Aberrant arrangement of vimentin undergoes malignancy accompanied by epithelial-mesenchymal-transition relating to the aberrant apoptotic cellular behavior in the tumor-niche. Restraint of the aberrant expression of vimentin on the plasma membrane of the malignant cell evokes a pertinent signal transduction pathway for healing that is an indication there must be a reverse path that reprograms cancer stem cells to normal organogenesis.

FoxO1 controls effector-to-memory transition and maintenance of functional CD8 T cell memory.

During a T cell response, naive CD8 T cells differentiate into effector cells. Subsequently, a subset of effector cells termed memory precursor effector cells further differentiates into functionally mature memory CD8 T cells. The transcriptional network underlying this carefully scripted process is not well understood. In this study, we report that the transcription factor FoxO1 plays an integral role in facilitating effector-to-memory transition and functional maturation of memory CD4 and CD8 T cells. We find that FoxO1 is not required for differentiation of effector cells, but in the absence of FoxO1, memory CD8 T cells displayed features of senescence and progressive attrition in polyfunctionality, which in turn led to impaired recall responses and poor protective immunity. These data suggest that FoxO1 is essential for maintenance of functional CD8 T cell memory and protective immunity. Under competing conditions in bone marrow chimeric mice, FoxO1 deficiency did not perturb clonal expansion or effector differentiation. Instead, FoxO1-deficient memory precursor effector cells failed to survive and form memory CD8 T cells. Mechanistically, FoxO1 deficiency perturbed the memory CD8 T cell transcriptome, characterized by pronounced alterations in the expression of genes that encode transcription factors (including Tcf7), effector molecules, cell cycle regulators, and proteins that regulate fatty acid, purine, and pyramidine metabolism and mitochondrial functions. We propose that FoxO1 is a key regulator that reprograms and steers the differentiation of effector cells to functionally competent memory cells. These findings have provided fundamental insights into the mechanisms that regulate the quality of CD8 T cell memory to intracellular pathogens.

Modulation of PKC-α promotes lineage reprogramming of committed B lymphocytes.

During hematopoietic lineage development, hematopoietic stem cells sequentially commit toward myeloid or lymphoid lineages in a tightly regulated manner, which under normal circumstances is irreversible. However, studies have established that targeted deletion of the B-lineage specific transcription factor, paired box gene 5 (Pax5), enables B cells to differentiate toward other hematopoietic lineages, in addition to generating progenitor B-cell lymphomas. Our previous studies showed that subversion of protein kinase C (PKC)-α in developing B cells transformed B-lineage cells. Here, we demonstrate that PKC-α modulation in committed CD19(+) B lymphocytes also promoted lineage conversion toward myeloid, NK-, and T-cell lineages upon Notch ligation. This occurred via a reduction in Pax5 expression resulting from a downregulation of E47, a product of the E2A gene. T-cell lineage commitment was indicated by the expression of T-cell associated genes Ptcra, Cd3e, and gene rearrangement at the Tcrb gene locus. Importantly, the lineage-converted T cells carried Igh gene rearrangements reminiscent of their B-cell origin. Our findings suggest that modulation of PKC-α induces hematopoietic-lineage plasticity in committed B-lineage cells by perturbing expression of critical B-lineage transcription factors, and deregulation of PKC-α activity/expression represents a potential mechanism for lineage trans-differentiation during malignancies.

Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells.

Ectopic expression of transcription factors can reprogram somatic cells to a pluripotent state. However, most of the studies used skin fibroblasts as the starting population for reprogramming, which usually take weeks for expansion from a single biopsy. We show here that induced pluripotent stem (iPS) cells can be generated from adult human adipose stem cells (hASCs) freshly isolated from patients. Furthermore, iPS cells can be readily derived from adult hASCs in a feeder-free condition, thereby eliminating potential variability caused by using feeder cells. hASCs can be safely and readily isolated from adult humans in large quantities without extended time for expansion, are easy to maintain in culture, and therefore represent an ideal autologous source of cells for generating individual-specific iPS cells.

Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice.

During mammary tumorigenesis, there is a profound thymic involution associated with severe depletion of the most abundant subset of thymocytes, CD4(+)CD8(+) immature cells, and an early arrest in at least two steps of T cell differentiation. Thymic atrophy that is normally related with aging has been observed in other model systems, including graft-vs-host disease (GVHD) and tumor development. However, the mechanisms involved in this phenomenon remain to be elucidated. Vascular endothelial growth factor (VEGF) has been associated with thymic involution, when expressed at high levels systemically. In thymuses of D1-DMBA-3 tumor-bearing mice, this growth factor is diminished relative to the level of normal thymuses. Interestingly, the expression of hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesis and B-cell differentiation, is profoundly down-regulated in thymuses of tumor bearers. In parallel, IL-7 and IL-15 mRNA, crucial cytokines involved in thymocytes development and cellular homeostasis, respectively, are also down-regulated in the thymuses of tumor hosts as compared to those of normal mice. Injection of HGF into mice implanted with mammary tumors resulted in normalization of thymic volume and levels of VEGF, IL-7 and IL-15. While, injections of IL-7 partially restored the thymic involution observed in the thymuses of tumor-bearing mice, injection of IL-15 did not have any significant effects. Our data suggest that the downregulation of HGF and IL-7 may play an important role in the thymic involution observed in tumor-bearing hosts.

MHC class II presentation of gp100 epitopes in melanoma cells requires the function of conventional endosomes and is influenced by melanosomes.

Many human solid tumors express MHC class II (MHC-II) molecules, and proteins normally localized to melanosomes give rise to MHC-II-restricted epitopes in melanoma. However, the pathways by which this response occurs have not been defined. We analyzed the processing of one such epitope, gp100(44-59), derived from gp100/Pmel17. In melanomas that have down-regulated components of the melanosomal pathway, but constitutively express HLA-DR*0401, the majority of gp100 is sorted to LAMP-1(high)/MHC-II(+) late endosomes. Using mutant gp100 molecules with altered intracellular trafficking, we demonstrate that endosomal localization is necessary for gp100(44-59) presentation. By depletion of the AP-2 adaptor protein using small interfering RNA, we demonstrate that gp100 protein internalized from the plasma membrane to such endosomes is a major source for gp100(44-59) epitope production. The gp100 trapped in early endosomes gives rise to epitopes that are indistinguishable from those produced in late endosomes but their production is less sensitive to inhibition of lysosomal proteases. In melanomas containing melanosomes, gp100 is underrepresented in late endosomes, and accumulates in stage II melanosomes devoid of MHC-II molecules. The gp100(44-59) presentation is dramatically reduced, and processing occurs entirely in early endosomes or stage I melanosomes. This occurrence suggests that melanosomes are inefficient Ag-processing compartments. Thus, melanoma de-differentiation may be accompanied by increased presentation of MHC-II restricted epitopes from gp100 and other melanosome-localized proteins, leading to enhanced immune recognition.

Receptor activator of NF-kappaB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells.

Epithelial-mesenchymal transition (EMT) in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor beta1 (TGFbeta1) and transcription factors including Snail and Slug. We utilized the ARCaP(E)/ARCaP(M) prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaP(E) cells, the highly tumorigenic mesenchymal ARCaP(M) and ARCaP(M1) variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaP(M) and ARCaP(M1) expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-kappaB Ligand (RANKL). We observed that both epidermal growth factor (EGF) plus TGFbeta1 treatment and Snail overexpression induced EMT in ARCaP(E) and LNCaP cells, and EMT was associated with increased expression of RANKL protein. Finally, we determined that the RANKL protein was functionally active, promoting osteoclastogenesis in vitro. Our results indicate that RANKL is a novel marker for EMT during prostate cancer progression. RANKL may function as a link between EMT, bone turnover, and prostate cancer skeletal metastasis.

Recent advancements towards the derivation of immune-compatible patient-specific human embryonic stem cell lines.

The derivation of human embryonic stem cell lines from blastocyst stage embryos, first achieved almost a decade ago, demonstrated the potential to prepare virtually unlimited numbers of therapeutically beneficial cells in vitro. Assuming that large-scale production of differentiated cells is attainable, it is imperative to develop strategies to prevent immune responses towards the grafted cells following transplantation. In this review, I will discuss recent advances in the production of pluripotent cell lines using three emerging techniques: somatic cell nuclear transfer into enucleated oocytes and zygotes, parthenogenetic activation of unfertilized oocytes and induction of pluripotency in somatic cells. Importantly, if these techniques can be harnessed for generating patient-specific pluripotent cell lines, then immunological processes are expected to be low or completely absent.