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1.
Cancer Sci ; 115(1): 48-58, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37879607

RESUMO

We previously reported that the inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor function of CD8+ T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8+ T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8+ T cells. In vitro treatment of CD8+ T cells with SCD1 inhibitors enhanced IFN-γ production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl-CoA acetyltransferase 1 (ACAT1), in CD8+ T cells. The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8+ T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor-bearing mice enhanced IFN-γ production of tumor-infiltrating CD8+ T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased. These results indicated that SCD1 suppressed effector functions of CD8+ T cells through the increased esterified cholesterol in an ACAT1-dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol. Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti-PD-1 antibody therapy or CAR-T cell therapy in mouse tumor models. Therefore, the SCD1-ACAT1 axis is regulating effector functions of CD8+ T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.


Assuntos
Neoplasias , Ácido Oleico , Camundongos , Animais , Ácido Oleico/farmacologia , Linfócitos T CD8-Positivos , Acetiltransferases , Colesterol , Estearoil-CoA Dessaturase
2.
Sci Rep ; 14(1): 20833, 2024 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-39242718

RESUMO

Despite widespread cervical cancer (CC) screening programs, low participation has led to high morbidity and mortality rates, especially in developing countries. Because early-stage CC often has no symptoms, a non-invasive and convenient diagnostic method is needed to improve disease detection. In this study, we developed a new approach for differentiating both CC and cervical intraepithelial neoplasia (CIN)2/3, a precancerous lesion, from healthy individuals by exploring CC fatty acid metabolic reprogramming. Analysis of public datasets suggested that various fatty acid metabolizing enzymes were expressed at higher levels in CC tissues than in normal tissues. Correspondingly, 11 free fatty acids (FFAs) showed significantly different serum levels in CC patient samples compared with healthy donor samples. Nine of these 11 FFAs also displayed significant alterations in CIN2/3 patients. We then generated diagnostic models using combinations of these FFAs, with the optimal model including stearic and dihomo-γ-linolenic acids. Receiver operating characteristic curve analyses suggested that this diagnostic model could detect CC and CIN2/3 more accurately than using serum squamous cell carcinoma antigen level. In addition, the diagnostic model using FFAs was able to detect patients regardless of clinical stage or histological type. Overall, the serum FFA diagnostic model developed in this study could be a powerful new tool for the non-invasive early detection of CC and CIN2/3.


Assuntos
Ácidos Esteáricos , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Humanos , Feminino , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/sangue , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/diagnóstico , Ácidos Esteáricos/sangue , Adulto , Ácido 8,11,14-Eicosatrienoico/sangue , Pessoa de Meia-Idade , Biomarcadores Tumorais/sangue , Curva ROC
3.
JNCI Cancer Spectr ; 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39302712

RESUMO

BACKGROUND: Although therapeutic HPV vaccines could offer a non-invasive treatment for patients with cervical intraepithelial neoplasia (CIN), none have been clinically implemented. Oral administration of the therapeutic HPV vaccine, IGMKK16E7, results in the histological regression of HPV16-positive CIN2/3 to normal (complete response: CR). Here, we investigated biomarkers that could predict CR after oral administration of IGMKK16E7. METHODS: Forty-two patients administered with high-dose oral IGMKK16E7 in a Phase I/II trial were included. Cervical-exfoliated cells were collected before administration. Gene expression of CD4, CD8, Foxp3, PD-1, CTLA-4, CD103, CD28, CD80, CD86, and PD-L1 in the cells were measured by quantitative RT-PCR. ROC curve analysis and Mann-Whitney tests were used to explore potential biomarkers. Pearson correlation coefficient analysis was used to correlate gene expression profiles with clinical outcome. RESULTS: The only predictive biomarker of vaccine response for which ROC curve analysis showed significant diagnostic performance with histological CR was CD86 (AUC 0.71, 95%XI 0.53-0.88, p = .020). CR patients had significantly lower CD86 expression (CD86-low) than non-CR patients (p = .035). The CR rate for CD86-low and CD86-high cases was 50% and 19%, respectively, and CD86-low cases had a significantly higher CR rate (p = .047). Compared to all patients, the CD86-low group had a 1.5-fold increase in CR rate. Gene expression of CD86 and CTLA-4 showed the strongest positive correlation with clinical outcomes in the non-CR group (p < .001). CONCLUSION: Low expression of CD86 in exfoliated cervical cells can be used as a pre-treatment biomarker to predict histological CR after IGMKK16E7 use.

4.
Cancer Res Commun ; 3(9): 1840-1852, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37712874

RESUMO

Ovarian cancer has a poor prognosis and is difficult to detect in early stages. Therefore, developing new diagnostic markers for early-stage ovarian cancer is critical. Here, we developed a diagnostic marker for early-stage ovarian cancer on the basis of fatty acid metabolism characteristics of cancer cells. The expression of various fatty acid metabolizing enzymes such as stearoyl-CoA desaturase 1 (SCD1) was altered in early-stage ovarian cancer tissue compared with that in normal ovarian tissue. Changes in the expression of fatty acid metabolizing enzymes, particularly SCD1, in cancer tissues were found to alter concentrations of multiple free fatty acids (FFA) in serum. We were the first to show that fatty acid metabolic characteristics in tissues are related to the FFA composition of serum. Surprisingly, patients with stage I/II ovarian cancer also showed significant changes in serum levels of eight FFAs, which can be early diagnostic markers. Finally, using statistical analysis, an optimal early diagnostic model combining oleic and arachidic acid levels, fatty acids associated with SCD1, was established and confirmed to have higher diagnostic power than CA125, regardless of histology. Thus, our newly developed diagnostic model using serum FFAs may be a powerful tool for the noninvasive early detection of ovarian cancer. SIGNIFICANCE: Measurement of serum FFA levels by changes in the expression of fatty acid metabolizing enzymes in tumor tissue would allow early detection of ovarian cancer. In particular, the SCD1-associated FFAs, oleic and arachidic acid, would be powerful new screening tools for early-stage ovarian cancer.


Assuntos
Ácidos Graxos não Esterificados , Neoplasias Ovarianas , Feminino , Humanos , Estearoil-CoA Dessaturase , Neoplasias Ovarianas/diagnóstico , Ácidos Graxos
5.
JNCI Cancer Spectr ; 7(6)2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-38001029

RESUMO

BACKGROUND: Although many human papillomavirus (HPV)-targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine. METHODS: In a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16-positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety. RESULTS: In per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7-specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner. CONCLUSION: This trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16-positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects. TRIAL REGISTRATION: jRCT2031190034.


Assuntos
Infecções por Papillomavirus , Vacinas contra Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Feminino , Humanos , Papillomavirus Humano 16 , Papillomavirus Humano , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Displasia do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/tratamento farmacológico
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