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BACKGROUND/AIM: Clear cell carcinoma is a prevalent histological type of ovarian cancer in East Asia, particularly in Japan, known for its resistance to chemotherapeutic agents and poor prognosis. ARID1A gene mutations, commonly found in ovarian clear cell carcinoma (OCCC), contribute to its pathogenesis. Recent data revealed that the ARID1A mutation is related to better outcomes of cancer immunotherapy. Thus, this study aimed to investigate the immunotherapy treatment susceptibility of OCCC bearing ARID1A mutations. MATERIALS AND METHODS: Expression of ARID1A was analyzed using western blotting in ovarian cancer cell lines. OCCC cell lines JHOC-9 and RMG-V were engineered to overexpress NY-ESO-1, HLA-A*02:01, and ARID1A. Sensitivity to chemotherapy and T cell receptor-transduced T (TCR-T) cells specific for NY-ESO-1 was assessed in ARID1A-restored cells compared to ARID1A-deficient wild-type cells. RESULTS: JHOC-9 cells and RMG-V cells showed no expression of ARID1A protein. Overexpression of ARID1A in JHOC-9 and RMG-V cells did not impact sensitivity to gemcitabine. While ARID1A overexpression decreased sensitivity to cisplatin in RMG-V cells, it had no such effect in JHOC-9 cells. ARID1A overexpression reduced the reactivity of NY-ESO-1-specific TCR-T cells, as observed by the IFNγ ESLIPOT assay. CONCLUSION: Cancer immunotherapy is an effective approach to target ARID1A-deficient clear cell carcinoma of the ovary.
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Adenocarcinoma de Células Claras , Proteínas de Unión al ADN , Neoplasias Ováricas , Linfocitos T Citotóxicos , Factores de Transcripción , Humanos , Femenino , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/inmunología , Adenocarcinoma de Células Claras/metabolismo , Linfocitos T Citotóxicos/inmunología , Línea Celular Tumoral , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/inmunología , Antígeno HLA-A2/genética , Antígeno HLA-A2/inmunología , Antígeno HLA-A2/metabolismo , Proteínas de la MembranaRESUMEN
BACKGROUND/AIM: Human gastric cancer stem-like cells (CSCs)/cancer-initiating cells can be identified as aldehyde dehydrogenase-high (ALDHhigh) cells. Cancer immunotherapy employing immune checkpoint blockade has been approved for advanced gastric cancer cases. However, the effectiveness of cancer immunotherapy against gastric CSCs/CICs remains unclear. This study aimed to investigate the susceptibility of gastric CSCs/CICs to immunotherapy. MATERIALS AND METHODS: Gastric CSCs/CICs were isolated as ALDHhigh cells using the human gastric cancer cell line, MKN-45. ALDHhigh clone cells and ALDHlow clone cells were isolated using the ALDEFLUOR assay. ALDH1A1 expression was assessed via qRT-PCR. Sphere-forming ability was evaluated to confirm the presence of CSCs/CICs. A model neoantigen, AP2S1, was over-expressed in ALDHhigh clone cells and ALDHlow clone cells, and susceptibility to AP2S1-specific TCR-T cells was assessed using IFNγ ELISPOT assay. RESULTS: Three ALDHhigh clone cells were isolated from MKN-45 cells. ALDHhigh clone cells exhibited a stable phenotype in in vitro culture for more than 2 months. The High-36 clone cells demonstrated the highest sphere-forming ability, whereas the Low-8 cells showed the lowest sphere-forming ability. High-36 cells exhibited lower expression of HLA-A24 compared to Low-8 cells. TCR-T cells specific for AP2S1 showed lower reactivity to High-36 cells compared to Low-8 cells. CONCLUSION: High-36 cells and Low-8 cells represent novel gastric CSCs/CICs and non-CSCs/CICs, respectively. ALDHhigh CSCs/CICs evade T cells due to lower expression of HLA class 1.
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Familia de Aldehído Deshidrogenasa 1 , Células Madre Neoplásicas , Neoplasias Gástricas , Linfocitos T Citotóxicos , Humanos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/patología , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Familia de Aldehído Deshidrogenasa 1/metabolismo , Familia de Aldehído Deshidrogenasa 1/genética , Línea Celular Tumoral , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Retinal-Deshidrogenasa/metabolismo , Escape del Tumor/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunologíaRESUMEN
The mortality rate of oral cancer has not improved over the past three decades despite remarkable advances in cancer therapies. Oral cancers contain a subpopulation of cancer stem cells (CSCs) that share characteristics associated with normal stem cells, including self-renewal and multi-differentiation potential. CSCs are tumorigenic, play a critical role in cancer infiltration, recurrence, and distant metastasis, and significantly contribute to drug resistance to current therapeutic strategies, including immunotherapy. Cytotoxic CD8+ T lymphocytes (CTLs) are key immune cells that effectively recognize peptide antigens presented by the major histocompatibility complex class I molecules. Increasing evidence suggests that cancer antigen-specific targeting by CTLs effectively regulates CSCs that drive cancer progression. In this study, we utilized data from public domains and performed various bioassays on human oral squamous cell carcinoma clinical samples and cell lines, including HSC-2 and HSC-3, to investigate the potential role of olfactory receptor family 7 subfamily C member 1 (OR7C1), a seven transmembrane G-protein-coupled olfactory receptor that is also expressed in nonolfactory tissues and was previously reported as a novel marker and target of colon cancer initiating cell-targeted immunotherapy, in CSC-targeted treatment against oral cancer. We found that the OR7C1 gene was expressed only in oral CSCs, and that CTLs reacted with human leukocyte antigen-A24-restricted OR7C1 oral CSC-specific peptides. Taken together, our findings suggest that OR7C1 represents a novel target for potent CSC-targeted immunotherapy in oral cancer.
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Carcinoma de Células Escamosas , Neoplasias de la Boca , Receptores Odorantes , Humanos , Receptores Odorantes/metabolismo , Carcinoma de Células Escamosas/patología , Neoplasias de la Boca/patología , Inmunoterapia , Linfocitos T Citotóxicos , Células Madre Neoplásicas/metabolismo , PéptidosRESUMEN
Despite the considerable success of cancer immunotherapy with immune checkpoint inhibitors, their nonspecific release of the immunosuppressive mechanism is often associated with immune-related adverse events (irAEs). irAEs significantly disturb patients' quality of life and can even be life-threatening. Therefore, the appropriate management of irAEs is crucial for the development of further reliable cancer immunotherapies. irAEs have the appearance of ordinary autoimmune diseases in one aspect but often have distinct features. Although the detailed pathogenesis of irAEs remains unclear, increasing numbers of studies have provided numerous clues. Here, we review the current knowledge on irAEs, particularly from an immunopathological basis.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Calidad de Vida , RadioinmunoterapiaRESUMEN
Thus far, there have been limited case reports on immunoglobulin G4-related autoimmune hepatitis (IgG4-AIH), and its clinical features have not been elucidated. We herein report a rare case of IgG4-AIH simultaneously concomitant with autoimmune pancreatitis (AIP). A 73-year-old female was admitted to our hospital for further investigation of elevated levels of liver transaminase and pancreatic enzymes. Her serological tests showed a high antinuclear antibody titer, and elevated IgG and IgG4 levels. Liver biopsy revealed interface hepatitis and bridging necrosis with IgG4-positive lymphoplasmacytic infiltration in the portal area. Moreover, contrast-enhanced computed tomography (CECT) showed pancreatic tail enlargement, and magnetic resonance cholangiopancreatography showed skipped narrowing of the main pancreatic duct in the pancreatic tail. Endoscopic ultrasonography-fine needle aspiration specimens showed no malignant cells. Based on these results, we diagnosed her with IgG4-AIH simultaneously concomitant with probable type 1 AIP. She was started on prednisolone (PSL) at 35 mg/d, and her symptoms and liver transaminase levels improved. One month after starting treatment, CECT showed improvement of pancreatic tail enlargement. She is maintained on 5 mg PSL/d and has been in remission for two years.
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Enfermedades Autoinmunes , Pancreatitis Autoinmune , Hepatitis Autoinmune , Anciano , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/tratamiento farmacológico , Biopsia con Aguja Fina , Pancreatocolangiografía por Resonancia Magnética , Femenino , Hepatitis Autoinmune/complicaciones , Hepatitis Autoinmune/tratamiento farmacológico , Humanos , Inmunoglobulina GRESUMEN
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
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Colitis/inmunología , Colon/patología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Mucosa Intestinal/patología , Neoplasias/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Biopsia , Colitis/inducido químicamente , Colitis/diagnóstico , Colitis/patología , Colon/inmunología , Femenino , Humanos , Mucosa Intestinal/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Estudios RetrospectivosRESUMEN
Mismatch repair protein deficiency (dMMR) is a favorable prognostic factor in colorectal cancer. It is also associated with aberrant expression of HLA class I molecules, which are required for cytotoxic T lymphocyte-mediated cancer immunotherapy. Because dMMR is frequently also found in endometrial cancers (ECs), we retrospectively investigated the expression of mismatch repair proteins and HLA class I molecules in 127 EC patients. In this study, EC patients being treated in our hospital were recruited from 2005 to 2009 and observed until December 2017. Lesion specimens were evaluated via immunohistochemistry for MSH6 and PMS2 (mismatch repair proteins) and HLA class I molecules. Expression of these molecules was statistically related to clinical and pathological factors and prognosis. dMMR was detected in 33 patients and did not correlate with the expression level of HLA class I molecules (P = 0.60). On the other hand, unexpectedly, multivariate analysis revealed that intact expression of HLA class I molecules was associated with p53 overexpression (P = 0.004). Neither dMMR nor decreased expression of HLA class I molecules were prognostic factors. These results are inconsistent with previous findings for colorectal cancer. A distinctive local tissue immune microenvironment would underlie the discrepancy in the results between EC and colorectal cancer.
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Biomarcadores de Tumor/deficiencia , Neoplasias Colorrectales/genética , Neoplasias Endometriales/genética , Regulación Neoplásica de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Reparación de la Incompatibilidad de ADN , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/cirugía , Endometrio/patología , Endometrio/cirugía , Femenino , Estudios de Seguimiento , Humanos , Histerectomía , Inmunohistoquímica , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/análisis , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/deficiencia , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Supervivencia sin Progresión , Estudios Retrospectivos , Salpingooforectomía , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Effective management of immune-related adverse events in patients receiving immunotherapy for cancer is problematic. In this report, we present the case of a 58-year-old man with advanced clear cell renal cell carcinoma who responded well to a combination of ipilimumab and nivolumab. However, after two courses of treatment, he developed fulminant hepatitis and died. An autopsy confirmed that the primary lesion in the left kidney was more than 99% necrotic with only six small residual tumor lesions. These lesions were infiltrated by large numbers of CD8-positive/TIA-1-positive lymphocytes. However, a metastatic lesion in the right kidney harbored few lymphocytes. Furthermore, the tumor cells in the metastatic lesion and one of the residual lesions showed decreased expression of HLA class I molecules, which are a prerequisite for cytotoxic T-lymphocyte-mediated immunotherapy in tumor cells. In this patient, more than 80% of hepatocytes were destroyed and the parenchyma was infiltrated with CD8-positive/TIA-1-positive lymphocytes. The patient had polyuria, which was attributed to neurohypophysitis caused by the infiltration of CD8-positive/TIA-1-positive lymphocytes. We believe that this is an instructive case for immuno-oncologists.
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Antineoplásicos Inmunológicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Inmunoterapia/efectos adversos , Ipilimumab/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Necrosis Hepática Masiva/inducido químicamente , Nivolumab/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Autopsia , Quimioterapia Combinada , Resultado Fatal , Hepatocitos/patología , Humanos , Ipilimumab/administración & dosificación , Riñón/patología , Linfocitos/patología , Masculino , Necrosis Hepática Masiva/patología , Persona de Mediana Edad , Necrosis , Nivolumab/administración & dosificación , Resultado del TratamientoRESUMEN
INTRODUCTION: Immune checkpoint inhibitors are now a standard therapeutic option for lung adenocarcinoma. However, Immune checkpoint inhibitors often induce various immune-related adverse events. CASE PRESENTATION: The patient was a 78-year-old woman with lung adenocarcinoma who had a partial response to pembrolizumab. During treatment, she complained of pollakiuria and nocturia with painful micturition. Histological analysis revealed infiltration of CD8-positive and/or TIA-1 cytotoxic granule-associated RNA binding protein-positive lymphocytes and programmed death-ligand 1 expression in the urothelium. A diagnosis of immune-related adverse event cystitis was made based on these clinical and pathological findings. The patient's subjective symptoms and findings on cystoscopy improved dramatically after treatment with prednisolone. CONCLUSION: Immune checkpoint inhibitors-induced cystitis is extremely rare. This report is the first to include an immunohistochemical analysis of the urothelial epithelium in immune-related adverse event cystitis and describes an instructive case.
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BACKGROUND/AIM: The tumor microenvironment (TME) balances tumor growth and suppression through humoral factors and cell-cell interactions. In oral squamous cell carcinoma (OSCC), TMEs have been associated with prognosis of cancer patients and are evaluated by microscopy; however, these methods of evaluation vary among studies. MATERIALS AND METHODS: To evaluate the TME, borderline microenvironment fibrosis (bMF) was evaluated histologically in 236 OSCC cases and used to determine the clinicopathological status. RESULTS: bMF was observed in 47% (110 in 236 cases) of OSCC cases and associated with higher T category, N category, stage, histological grade and mode of invasion. bMF-positive was related to overall survival (OS) and progression-free survival (PFS). Multivariate analysis revealed that bMF-positive was an independent factor for OS in all cases [n=226; HR=1.683 (1.018-2.781); p=0.042], especially in T1+T2 cases [n=186; HR=1.926 (1.079-3.440); p=0.024], and PFS in all cases [n=226; HR=2.254 (1.397-3.637); p=0.001]. CONCLUSION: bMF may act as a novel biomarker for OSCC.
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Biomarcadores de Tumor , Carcinoma de Células Escamosas/patología , Neoplasias de la Boca/patología , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Fibrosis , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: The surgical resection of craniovertebral junction(CVJ)meningioma is challenging because of the neighboring brainstem, lower cranial nerves, and vertebral artery(VA). Moreover, encasement of the VA by the tumor can raise the risk of complications and require cautious manipulation during surgery. CASE: A 46-year-old woman presented with a one-year history of neck pain. She had temporal hemiplegia and numbness on her left side. Magnetic resonance imaging(MRI)showed a CVJ meningioma pushing the brainstem from the right vertebral side and encasing the right VA. Digital subtraction angiography(DSA)showed two feeding arteries arising from the right VA and a sunburst sign. The right VA was the dominant side but did not have the right posterior inferior cerebellar artery(PICA). The anterior spinal artery(ASA)was dominant in the left VA. We performed a balloon test occlusion(BTO)for 20 min and it did not cause any complications;therefore, we occluded the VA using endovascular coils. After 4 days, we removed the meningioma in the prone position, using a far-lateral approach and C1-laminectomy. The laterally located meningioma pushed the brainstem. After detaching the tumor from the dura, we cut the encased VA and the tumor was resected safely(Simpson grade II). Postoperatively, she developed temporal thermal hypoalgesia on the left side of her body. Magnetic resonance imaging showed a microinfarction in the medulla. CONCLUSION: If the VA test occlusion provides a clear result, pre-operative endovascular sacrifice of the VA encased by CVJ meningioma is a feasible treatment strategy.
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Embolización Terapéutica , Neoplasias Meníngeas , Neoplasias de la Médula Espinal , Femenino , Humanos , Persona de Mediana Edad , Procedimientos Quirúrgicos Vasculares , Arteria VertebralRESUMEN
Langerhans cell sarcoma (LCS) and quintuple cancers are extremely rare. In this report, a case of quintuple cancers including LCS was described. An 80-year-old man had squamous cell carcinoma of the nasal skin, colon and rectum adenocarcinomas, and T-cell/histiocyte-rich large B-cell lymphoma. As swelling of multiple submental lymph nodes was observed, fine-needle aspiration was carried out. Many large cells with high-grade nuclear atypia and abundant cytoplasm were observed. Lymphocytes and eosinophils were observed in the background. Although a malignant tumor was suspected, a definite diagnosis could not be made. In a biopsy sample, the tumor cells were positive for vimentin, CD68, S-100, CD1a, and CD163 and negative for epithelial, lymphocyte, and melanoma markers in immunohistochemistry. A diagnosis of LCS was made from the immunohistochemical findings and high mitotic rate with atypical forms. The patient died about 2 months after the first medical examination. Metastasis of LCS was confirmed in many organs by autopsy. LCS has a poor prognosis. In cases with the above-described cytological findings, LCS should be added to the list of differential diagnosis. The cytological findings presented here may be useful for determining appropriate clinical management such as staging of the disease and follow-up of the neoplasm. Diagn. Cytopathol. 2017;45:441-445. © 2017 The Authors Diagnostic Cytopathology Published by Wiley Periodicals, Inc.
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Adenocarcinoma/diagnóstico , Neoplasias Colorrectales/diagnóstico , Sarcoma de Células de Langerhans/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células T/diagnóstico , Neoplasias Nasales/diagnóstico , Neoplasias Cutáneas/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patología , Anciano de 80 o más Años , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biopsia con Aguja Fina , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resultado Fatal , Humanos , Sarcoma de Células de Langerhans/genética , Sarcoma de Células de Langerhans/patología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células T/genética , Linfoma de Células T/patología , Masculino , Neoplasias Nasales/genética , Neoplasias Nasales/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Vimentina/genética , Vimentina/metabolismoRESUMEN
Human cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be isolated as side population (SP) cells, aldehyde dehydrogenase high (ALDHhigh) cells or cell surface marker-positive cells including CD44+ cells and CD133+ cells. CSCs/CICs and non-CSCs/CICs are unstable in in vitro culture, and CSCs/CICs can differentiate into non-CSCs/CICs and some non-CSCs/CICs can dedifferentiate into CSCs/CICs. Therefore, experiments using a large amount of CSCs/CICs are technically very difficult. In this study, we isolated single cell clones from SP cells and main population (MP) cells derived from the human colon cancer cell line SW480. SP analysis revealed that SP clone cells had relatively high percentages of SP cells, whereas MP clone cells showed very few SP cells, and the phenotypes were sustainable for more than 2 months of in vitro culture. Xenograft transplantation revealed that SP clone cells have higher tumor-initiating ability than that of MP clone cells and SP clone cell showed higher chemo-resistance compared with MP clone cells. These results indicate that SP clone cells derived from SW480 cells are enriched with CSCs/CICs, whereas MP clone cells are pure non-CSCs/CICs. SP clone cells and MP clone cells are a very stable in vitro CSC/CIC-enriched and non-CSC/CIC model for further analysis.
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Neoplasias del Colon/patología , Células Madre Neoplásicas/fisiología , Células de Población Lateral/fisiología , Animales , Ciclo Celular , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trasplante de Neoplasias , Células Madre Neoplásicas/trasplante , Células de Población Lateral/trasplanteRESUMEN
PURPOSE: Cancer-initiating cells (CICs) are thought to be essential for tumor maintenance, recurrence, and distant metastasis, and they are therefore reasonable targets for cancer therapy. Cancer immunotherapy is a novel approach to target cancer. In this study, we aimed to establish novel CIC-targeting immunotherapy. EXPERIMENTAL DESIGN: Colorectal cancer (CRC) CICs were isolated as side population (SP) cells. The gene expression profile of CRC CICs was analyzed by cDNA microarray and RT-PCR. Protein expression of olfactory receptor family 7 subfamily C member 1 (OR7C1) were analyzed by Western blot and immunohistochemical staining. The functions of OR7C1 were analyzed by gene overexpression and gene knockdown using siRNAs. OR7C1-positive cells were isolated by a flow cytometer and analyzed. CTLs specific for OR7C1 peptide were generated, and the antitumor effect was addressed by mice adoptive transfer model. RESULTS: OR7C1 has essential roles in the maintenance of colon CICs, and the OR7C1-positive population showed higher tumorigenicity than that of the OR7C1-negative population, indicating that OR7C1 is a novel functional marker for colon CIC. Immunohistochemical staining revealed that OR7C1 high expression was correlated with poorer prognosis in CRC patients. OR7C1-derived antigenic peptide-specific CTLs showed specific cytotoxicity for CICs, and an OR7C1-specific CTL clone showed a greater antitumor effect than did a CTL clone targeting all cancer cells in a CTL adoptive transfer mouse model. CONCLUSIONS: OR7C1 is a novel marker for colon CICs and can be a target of potent CIC-targeting immunotherapy. Clin Cancer Res; 22(13); 3298-309. ©2016 AACR.
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Adenocarcinoma/terapia , Biomarcadores de Tumor/inmunología , Neoplasias del Colon/terapia , Inmunoterapia/métodos , Células Madre Neoplásicas/inmunología , Receptores Odorantes/inmunología , Linfocitos T Citotóxicos/inmunología , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Animales , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Células HT29 , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Pronóstico , Interferencia de ARN , ARN Interferente Pequeño/genética , Receptores Odorantes/biosíntesis , Receptores Odorantes/genética , Esferoides Celulares , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Identification of antigenic peptides derived from tumor-associated antigens (TAA) enables cancer vaccine therapy using antigenic peptides. Here, we summarize the design of antigenic peptides and induction of cytotoxic T lymphocytes (CTL) using antigenic peptides and validation of CTL.
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Antígenos de Neoplasias/inmunología , Epítopos de Linfocito T/inmunología , Linfocitos T Citotóxicos/inmunología , Células Presentadoras de Antígenos/inmunología , Células Clonales/citología , Células Clonales/inmunología , Antígenos HLA/inmunología , Humanos , Interferón gamma/metabolismo , Reproducibilidad de los Resultados , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/metabolismoRESUMEN
The aim of the present study was to establish cancer stem-like cell/cancer-initiating cell (CSC/CIC)-targeting immunotherapy. The CSC/CIC are thought to be essential for tumor maintenance, recurrence and distant metastasis. Therefore they are reasonable targets for cancer therapy. In the present study, we found that a heat shock protein (HSP) 40 family member, DnaJ (Hsp40) homolog, subfamily B, member 8 (DNAJB8), is preferentially expressed in CSC/CIC derived from colorectal cancer (CRC) cells rather than in non-CSC/CIC. Overexpression of DNAJB8 enhanced the expression of stem cell markers and tumorigenicity, indicating that DNAJB8 has a role in CRC CSC/CIC. A DNAJB8-specific cytotoxic T lymphocyte (CTL) response could be induced by a DNAJB8-derived antigenic peptide. A CTL clone specific for DNAJB8 peptide showed higher killing activity to CRC CSC/CIC compared with non-CSC/CIC, and CTL adoptive transfer into CRC CSC/CIC showed an antitumor effect in vivo. Taken together, the results indicate that DNAJB8 is expressed and has role in CRC CSC/CIC and that DNAJB8 is a novel target of CRC CSC/CIC-targeting immunotherapy.
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Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Proteínas del Choque Térmico HSP40/biosíntesis , Inmunoterapia , Chaperonas Moleculares/biosíntesis , Proteínas del Tejido Nervioso/biosíntesis , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Biomarcadores de Tumor/inmunología , Línea Celular Tumoral , Neoplasias del Colon/terapia , Regulación Neoplásica de la Expresión Génica/inmunología , Proteínas del Choque Térmico HSP40/genética , Humanos , Chaperonas Moleculares/genética , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/terapia , Células Madre Neoplásicas/inmunología , Proteínas del Tejido Nervioso/genética , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Cancer stem-like cells (CSCs)/cancer-initiaiting cells (CICs) are defined as a small population of cancer cells that have self-renewal capacity, differentiation potential and high tumor-initiating ability. CSCs/CICs of ovarian cancer have been isolated by side population (SP) analysis, ALDEFLUOR assay and using cell surface markers. However, these approaches are not definitive markers for CSCs/CICs, and it is necessary to refine recent methods for identifying more highly purified CSCs/CICs. In this study, we analyzed SP cells and aldehyde dehydrogenese bright (ALDH(Br)) cells from ovarian cancer cells. Both SP cells and ALDH(Br) cells exhibited higher tumor-initiating ability and higher expression level of a stem cell marker, sex determining region Y-box 2 (SOX2), than those of main population (MP) cells and ALDH(Low) cells, respectively. We analyzed an SP and ALDH(Br) overlapping population (SP/ALDH(Br)), and the SP/ALDH(Br) population exhibited higher tumor-initiating ability than that of SP cells or ALDH(Br) cells, enabling initiation of tumor with as few as 10(2) cells. Furthermore, SP/ADLH(Br) population showed higher sphere-forming ability, cisplatin resistance, adipocyte differentiation ability and expression of SOX2 than those of SP/ALDH(Low), MP/ALDH(Br) and MP/ALDH(Low) cells. Gene knockdown of SOX2 suppressed the tumor-initiation of ovarian cancer cells. An SP/ALDH(Br) population was detected in several gynecological cancer cells with ratios of 0.1% for HEC-1 endometrioid adenocarcinoma cells to 1% for MCAS ovary mucinous adenocarcinoma cells. Taken together, use of the SP and ALDH(Br) overlapping population is a promising approach to isolate highly purified CSCs/CICs and SOX2 might be a novel functional marker for ovarian CSCs/CICs.
Asunto(s)
Aldehído Deshidrogenasa/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/metabolismo , Células de Población Lateral/metabolismo , Aldehído Deshidrogenasa/genética , Animales , Línea Celular Tumoral , Femenino , Citometría de Flujo , Xenoinjertos , Humanos , Ratones , Neoplasias Ováricas/genética , Fenotipo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Esferoides Celulares , Células Tumorales CultivadasRESUMEN
Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cancer cells that have high tumorigenicity. Furthermore, CSCs/CICs are resistant to several cancer therapies, and CSCs/CICs are therefore thought to be responsible for cancer recurrence after treatment and distant metastasis. In epithelial ovarian cancer (EOC) cases, disease recurrence after chemotherapy is frequently observed, suggesting ovarian CSCs/CICs are involved. There are four major histological subtypes in EOC, and serous adenocarcinoma and clear cell adenocarcinoma are high-grade malignancies. We therefore analyzed ovarian CSCs/CICs from ovarian carcinoma cell lines (serous adenocarcinoma and clear cell adenocarcinoma) and primary ovarian cancer cells in this study. We isolated ovarian CSCs/CICs as an aldehyde dehydrogenase 1 high (ALDH1(high)) population from 6 EOC cell lines (3 serous adenocarcinomas and 3 clear cell adenocarcinomas) by the ALDEFLUOR assay. ALDH1(high) cells showed greater sphere-forming ability, higher tumorigenicity and greater invasive capability, indicating that ovarian CSCs/CICs are enriched in ALDH1(high) cells. ALDH1(high) cells could also be isolated from 8 of 11 primary ovarian carcinoma samples. Immunohistochemical staining revealed that higher ALDH1 expression levels in ovary cancer cases are related to poorer prognosis in both serous adenocarcinoma cases and clear cell adenocarcinoma cases. Taken together, the results indicate that ALDH1 is a marker for ovarian CSCs/CICs and that the expression level of ALDH1 might be a novel biomarker for prediction of poor prognosis.