Recent studies have shown that tumor cells acquire escape mechanisms to evade host immunity in the tumor microenvironment. Two key immune checkpoint pathways mediated by immunosuppressive ...co-signaling, the first via programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-1/PD-L1) and the second via CTLA-4 and B7 (CTLA-4/B7), have been previously described. Several clinical trials have revealed an outstanding anti-tumor efficacy of immune checkpoint inhibitors (anti-CTLA-4 antibody, anti-PD-1 antibody and/or anti-PD-L1 antibody) in patients with various types of solid malignancies, including non-small cell lung cancer, melanoma, renal cell cancer and ovarian cancer. In this review, we examine pre-clinical studies that described the local immune status and immune checkpoint signals in ovarian cancer, highlight recent clinical trials that evaluated immune checkpoint inhibitors against ovarian cancer and discuss the clinical issues regarding immune checkpoint inhibitors.
Homologous recombination repair (HRR) pathway deficiency (HRD) is involved in the tumorigenesis and progression of high-grade serous ovarian carcinoma (HGSOC) as well as in the sensitivity to ...platinum chemotherapy drugs. In this study, we obtained data from The Cancer Genome Atlas (TCGA) on HGSOC and identified scores for the loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions, and calculated the HRD score. We then investigated the relationships among the score, genetic/epigenetic alterations in HRR-related genes, and the clinical data. We found that BRCA1/2 mutations were enriched in the group with HRD scores ≥63. Compared with the groups with scores ≤62, this group had a good prognosis; we thus considered HRD scores ≥63 to be the best cutoff point for identifying HRD cases in HGSOC. Classification of HGSOC cases by the HRD status revealed a better prognosis for HRD cases caused by genetic alterations (genetic HRD) than those caused by epigenetic changes and those caused by undetermined reasons (p = 0.0002). Among cases without macroscopic residual tumors after primary debulking surgery, 11 of 12 genetic HRD cases survived after the median observation period of 6.6 years, showing remarkably high survival rates (p = 0.0059). In conclusion, HGSOC can be classified into subtypes with different prognoses according to HRD status. This classification could be useful for personalized HGSOC treatment.
The mechanism of resistance development to anti-VEGF therapy in ovarian cancer is unclear. We focused on the changes in tumour immunity post anti-VEGF therapy.
The frequencies of immune cell ...populations and hypoxic conditions in the resistant murine tumours and clinical samples were examined. The expression profiles of both the proteins and genes in the resistant tumours were analysed. The impact of granulocyte-monocyte colony-stimulating factor (GM-CSF) expression on myeloid-derived suppressor cell (MDSC) function in the resistant tumours was evaluated.
We found a marked increase and reduction in the number of Gr-1 + MDSCs and CD8 + lymphocytes in the resistant tumour, and the MDSCs preferentially infiltrated the hypoxic region. Protein array analysis showed upregulation of GM-CSF post anti-VEGF therapy. GM-CSF promoted migration and differentiation of MDSCs, which inhibited the CD8 + lymphocyte proliferation. Anti-GM-CSF therapy improved the anti-VEGF therapy efficacy, which reduced the infiltrating MDSCs and increased CD8 + lymphocytes. In immunohistochemical analysis of clinical samples, GM-CSF expression and MDSC infiltration was enhanced in the bevacizumab-resistant case.
The anti-VEGF therapy induces tumour hypoxia and GM-CSF expression, which recruits MDSCs and inhibits tumour immunity. Targeting the GM-CSF could help overcome the anti-VEGF therapy resistance in ovarian cancers.
Although immune-based cancer treatment has long been investigated, only recently has its clinical efcacy equaled or surpassed conventional chemo-therapy. This striking effect of novel immune therapy ...has been achieved by drugs called immune checkpoint inhibitors, especially antibodies to block the PD-L1/PD-1 (programmed cell death ligand-1/programmed cell death-1) immune signal.
Recent studies showed that tumor cells ‘edit’ host immunity in several ways to evade immune defenses in the tumor microenvironment. This phenomenon is called “cancer immune escape.” One of the most ...important components in this system is an immunosuppressive co-signal (immune checkpoint) mediated by the PD-1 receptor and its ligand, PD-L1. PD-1 is mainly expressed on activated T cells, whereas PD-L1 is expressed on several types of tumor cells. Preclinical studies have shown that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. Several clinical trials of PD-1/PD-L1 signal-blockade agents have exhibited dramatic antitumor efficacy in patients with certain types of solid or hematological malignancies. In this review, we highlight recent clinical trials using anti-PD-1 or anti-PD-L1 antibodies against several types of malignancies, including a trial conducted in our department, and describe the clinical perspectives and issues regarding the PD-1/PD-L1 blockade in cancer treatment.
Snail is a major transcriptional factor that induces epithelial-mesenchymal transition (EMT). In this study, we explore the effect of Snail on tumor immunity. Snail knockdown in mouse ovarian cancer ...cells suppresses tumor growth in immunocompetent mice, associated with an increase of CD8
tumor-infiltrating lymphocytes and a decrease of myeloid-derived suppressor cells (MDSCs). Snail knockdown reduces the expression of CXCR2 ligands (CXCL1 and CXCL2), chemokines that attract MDSCs to the tumor via CXCR2. Snail upregulates CXCR ligands through NF-kB pathway, and most likely, through direct binding to the promoters. A CXCR2 antagonist suppresses MDSC infiltration and delays tumor growth in Snail-expressing mouse tumors. Ovarian cancer patients show elevated serum CXCL1/2, which correlates with Snail expression, MDSC infiltration, and short overall survival. Thus, Snail induces cancer progression via upregulation of CXCR2 ligands and recruitment of MDSCs. Blocking CXCR2 represents an immunological therapeutic approach to inhibit progression of Snail-high tumors undergoing EMT.
Programmed death-1 receptor (PD-L1, B7-H1) and programmed cell death protein 1 (PD-1) pathway blockade is a promising therapy for treating cancer. However, the mechanistic contribution of host and ...tumor PD-L1 and PD-1 signaling to the therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1- and PD-1-deficient mice. In contrast, neither knockout nor overexpression of PD-L1 in tumor cells had an effect on PD-L1 blockade efficacy. Human and murine studies showed high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti-PD-1 alone or in combination with anti-CTLA-4. Thus, PD-L1-expressing dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade.
Abstract
Endometrial cancer (EC) is the most common gynecological tumor in developed countries, and preoperative risk stratification is essential for personalized medicine. There have been several ...radiomics studies for noninvasive risk stratification of EC using MRI. Although tumor segmentation is usually necessary for these studies, manual segmentation is not only labor-intensive but may also be subjective. Therefore, our study aimed to perform the automatic segmentation of EC on MRI with a convolutional neural network. The effect of the input image sequence and batch size on the segmentation performance was also investigated. Of 200 patients with EC, 180 patients were used for training the modified U-net model; 20 patients for testing the segmentation performance and the robustness of automatically extracted radiomics features. Using multi-sequence images and larger batch size was effective for improving segmentation accuracy. The mean Dice similarity coefficient, sensitivity, and positive predictive value of our model for the test set were 0.806, 0.816, and 0.834, respectively. The robustness of automatically extracted first-order and shape-based features was high (median ICC = 0.86 and 0.96, respectively). Other high-order features presented moderate-high robustness (median ICC = 0.57–0.93). Our model could automatically segment EC on MRI and extract radiomics features with high reliability.
To clarify the impact of blood pressure (BP) management ranges on pregnancy outcomes, we conducted a multicenter retrospective analysis of 215 women with singleton pregnancies diagnosed with ...essential hypertension either before or within 14 weeks of gestation. Patients were classified according to systolic BP (sBP; <130, 130-139, 140-159, and ≥160 mmHg) or diastolic BP (dBP; <80, 80-89, 90-109, and ≥110 mmHg) at 8-11, 12-15, and 16-19 weeks of gestation. The risk of early-onset superimposed preeclampsia and small-for-gestational-age neonates was assessed in each BP group. Moreover, a subgroup analysis was performed in 144 eligible patients whose BP was measured at both 12-13 and 14-15 weeks of gestation. At 16-19 weeks of gestation, higher sBP significantly increased the incidence of early-onset superimposed preeclampsia (13.3%, 24.6%, 32.2% and 75.0%, respectively) and small-for-gestational-age neonates (6.0%, 13.1%, 16.9% and 50.0%, respectively). Multivariate logistic regression analyses showed that women with sBP < 130 mmHg at 16-19 weeks of gestation had a significantly lower risk of early-onset superimposed preeclampsia than women with sBP of 140-159 mmHg. Subgroup analyses also showed that even at 14-15 weeks of gestation, sBP < 130 mmHg was associated with a significantly lower risk of early-onset superimposed preeclampsia than an sBP of 140-159 mmHg. In conclusion, sBP < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed preeclampsia in women with chronic hypertension.
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