Expression levels of a gene signature in hiPSC associated with lung adenocarcinoma stem cells and its capability in eliciting specific antitumor immune‐response in a humanized mice model
Abstract:Background: Previous studies have reported that cancer stem cells (CSCs) play a key role in tumorigenesis, metastasis, and recurrence. CSC-based vaccination confers better protection in tumor cells. However, isolation and cultivation of CSCs are difficult. This study aimed to explore the similarities between CSCs and induced pluripotent stem cells (iPSCs). Methods: ALDH1+ cancer stem cells were isolated from lung adenocarcinoma patients and their gene expression patterns compared with human induced pluripotent… Show more
“…The concept of using embryonic stem cells (ESCs) or iPSCs as a prophylactic cancer vaccine has been evaluated in multiple studies in different murine tumor models, including models for lung cancer (Dong et al, 2010;Wang et al, 2020;Yaddanapudi et al, 2012), melanoma (Gąbka-Buszek et al, 2020Kooreman et al, 2018), ovarian cancer (Zhang et al, 2012), colon cancer (Li et al, 2009), and mesothelioma (Kooreman et al, 2018). These studies show the efficacy of ESC/iPSC-based cancer vaccines in preventing tumor development in mouse models in those cancer types and show the potential of these vaccines as promising prophylactic cancer vaccines, suggesting the need of testing these vaccines in more preclinical models and eventually clinical settings.…”
Induced pluripotent stem cells (iPSCs) and cancer cells share cellular similarities and transcriptomic profiles. Here, we show that an iPSCbased cancer vaccine, comprised of autologous iPSCs and CpG, stimulated cytotoxic antitumor CD8 + T cell effector and memory responses, induced cancer-specific humoral immune responses, reduced immunosuppressive CD4 + T regulatory cells, and prevented tumor formation in 75% of pancreatic ductal adenocarcinoma (PDAC) mice. We demonstrate that shared gene expression profiles of ''iPSC-cancer signature genes'' and others are overexpressed in mouse and human iPSC lines, PDAC cells, and multiple human solid tumor types compared with normal tissues. These results support further studies of iPSC vaccination in PDAC in preclinical and clinical models and in other cancer types that have low mutational burdens.
“…The concept of using embryonic stem cells (ESCs) or iPSCs as a prophylactic cancer vaccine has been evaluated in multiple studies in different murine tumor models, including models for lung cancer (Dong et al, 2010;Wang et al, 2020;Yaddanapudi et al, 2012), melanoma (Gąbka-Buszek et al, 2020Kooreman et al, 2018), ovarian cancer (Zhang et al, 2012), colon cancer (Li et al, 2009), and mesothelioma (Kooreman et al, 2018). These studies show the efficacy of ESC/iPSC-based cancer vaccines in preventing tumor development in mouse models in those cancer types and show the potential of these vaccines as promising prophylactic cancer vaccines, suggesting the need of testing these vaccines in more preclinical models and eventually clinical settings.…”
Induced pluripotent stem cells (iPSCs) and cancer cells share cellular similarities and transcriptomic profiles. Here, we show that an iPSCbased cancer vaccine, comprised of autologous iPSCs and CpG, stimulated cytotoxic antitumor CD8 + T cell effector and memory responses, induced cancer-specific humoral immune responses, reduced immunosuppressive CD4 + T regulatory cells, and prevented tumor formation in 75% of pancreatic ductal adenocarcinoma (PDAC) mice. We demonstrate that shared gene expression profiles of ''iPSC-cancer signature genes'' and others are overexpressed in mouse and human iPSC lines, PDAC cells, and multiple human solid tumor types compared with normal tissues. These results support further studies of iPSC vaccination in PDAC in preclinical and clinical models and in other cancer types that have low mutational burdens.
“…The choice for these SMs was based on our previous observation that salicylic diamines can selectively induce apoptosis in leukemia and lymphoma cells and even overcome multidrug resistance 43 , 44 . Since PSCs share some characteristics with cancer stem cells 45 – 47 , we reasoned that these compounds might also exert selective toxicity against PSCs but not their differentiated derivatives. Figure 1 Toxicity of small molecules SM1-SM16 against miPSC line aPIG-AT25.…”
Clinical translation of pluripotent stem cell (PSC) derivatives is hindered by the tumorigenic risk from residual undifferentiated cells. Here, we identified salicylic diamines as potent agents exhibiting toxicity to murine and human PSCs but not to cardiomyocytes (CMs) derived from them. Half maximal inhibitory concentrations (IC50) of small molecules SM2 and SM6 were, respectively, 9- and 18-fold higher for human than murine PSCs, while the IC50 of SM8 was comparable for both PSC groups. Treatment of murine embryoid bodies in suspension differentiation cultures with the most effective small molecule SM6 significantly reduced PSC and non-PSC contamination and enriched CM populations that would otherwise be eliminated in genetic selection approaches. All tested salicylic diamines exerted their toxicity by inhibiting the oxygen consumption rate (OCR) in PSCs. No or only minimal and reversible effects on OCR, sarcomeric integrity, DNA stability, apoptosis rate, ROS levels or beating frequency were observed in PSC-CMs, although effects on human PSC-CMs seemed to be more deleterious at higher SM-concentrations. Teratoma formation from SM6-treated murine PSC-CMs was abolished or delayed compared to untreated cells. We conclude that salicylic diamines represent promising compounds for PSC removal and enrichment of CMs without the need for other selection strategies.
“…These results may suggest that the tumorigenic risk and immunogenicity of iPSCs can be utilized as advantages to generate iPSC-based cancer vaccines, which may exhibit potential usage as auxiliary therapy after surgery. Another parallel study demonstrated that iPSC had similar gene expression patterns with lung adenocarcinoma stem cells and could provoke anti-tumor immunity in humanized mice model [154]. Very recently, Gąbka-Buszek et al combined the whole-cell melanoma vaccine with stem cells, and demonstrated the increased effectiveness of the mixed cells in anti-tumor immunity.…”
Section: Possible Application Of Ipsc Technology In Developing Cancermentioning
Induced pluripotent stem cells (iPSCs) are mainly characterized by their unlimited proliferation abilities and potential to develop into almost any cell type. The creation of this technology has been of great interest to many scientific fields, especially regenerative biology. However, concerns about the safety of iPSC application in transplantation have arisen due to the tumorigenic and immunogenic properties of iPSCs. This review will briefly introduce the developing history of somatic reprogramming and applications of iPSC technology in regenerative medicine. In addition, the review will highlight two challenges to the efficient usage of iPSCs and the underlying mechanisms of these challenges. Finally, the review will discuss the expanding application of iPSC technology in cancer immunotherapy as a potential cancer vaccine and its advantages in auxiliary treatment compared with oncofetal antigen-based and embryonic stem cell (ESC)-based vaccines.
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