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  • 1
    In: Advances in Radiation Oncology, Elsevier BV, Vol. 8, No. 6 ( 2023-11), p. 101260-
    Type of Medium: Online Resource
    ISSN: 2452-1094
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2847724-8
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  • 2
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e21203-e21203
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e21203-e21203
    Abstract: e21203 Background: Radiotherapy (RT), surgical resection (SR), and immunotherapy (IT) as main therapies in lung cancer have either suppressive or stimulatory effects on the immune system. It’s still unclear the mechanism involved in the systemic changes of immune cells in the blood. Peripheral blood lymphocyte subpopulations were useful markers for evaluating immune response in tumor patients. Hence, we aimed to systematically investigate the alteration of lymphocyte subpopulations during the local therapies to evaluate antitumor treatment effects. Methods: Blood samples were obtained EDTA coated tubes and then centrifuged gently for white blood cell separation. The white blood cells in 10% DMSO and 90% FBS were frozen slowly in -80°C refrigerator. The following fluorochrome-conjugated surface and nuclear antibodies were used in the lymphocyte subtyping: CD11b, CD45, CD19, CD3, CD56, CD4, CD8a, CD25,CD127 and FOXP3. The staining cells were detected in the BD FACS machine and data were analyzed by the paired T-test. The percentage of Lymphocytes, Myeloid cells, B cells, T cells, Treg, CD8+ T cells, CD4+ T cells, NK cells, and NKT were examined. Results: Between July 2019 and January 2020, a total of 176 patients eligible, including 135 RT patients and 29 SR patients,12 IT patients, with both blood collection with both Pre, During and End therapies. Before local therapies, the percentage of total T cells in the RT group was significantly higher than SR (RT v.s SR mean:64.1 v.s 55.3, P = 0.02) while CD8+ T cells (RT v.s SR mean:28.2 v.s 34.5, P = 0.04)and Tregs (RT v.s SR mean:0.0 v.s 0.1, P = 0.055) were lower. The baseline level of T cells and their subtypes showed a significant difference in these two group patients. After local therapies, myeloid cells, lymphocytes, CD4+ T cells, CD8+ T cells, NK cells were significant different. There is no significant difference due to the smaller number of IT patients. In the RT group, lymphocytes (Pre-RT v.s End-RT mean:75.2 v.s 54.3, P = 0.004) and B cells (Pre-RT v.s End-RT mean:12.6 v.s 8.0, P = 0.03) were significantly decreased while other subpopulations didn’t show any significant difference after RT. Interestingly, in the SR group, there was a significant increase in CD4+ T cells (mean:59.0 v.s 62.1, p = 0.02) a trend of reduction in CD8+ T cells (mean:34.5 v.s 32.0, p = 0.055) after SR. In addition, there was an increased trend of Tregs after IT. Conclusions: There are some different patterns of distribution in subtypes of leukocytes in operable and inoperable patients and between different therapies. All RT, SR and IT changed the distribution of peripheral blood lymphocyte subpopulations. Further validation study is warranted to validate our findings particularly in circulating lymphocytes and B cells as a marker to evaluate immune status after RT, CD4+ T cells and CD8+ T cells after SR, Tregs after IT, as well as their relationship with tumor microenvironment and implication for personalized care.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e17523-e17523
    Abstract: e17523 Background: Human papillomavirus negative (HPV-) cervical cancer is a rare type of cervical cancer whose tumor immune microenvironment is still unclear. In this study, by single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) analysis of HPV-cervical cancer, we discovered and characterized a novel cell subtype with the ability to promote tumor immune escape, which we called macrophage-tumor fusion cells. Methods: scRNA-seq and ST were integrated to analyze the newly diagnosed HPV- cervical cancer tumor tissue. Seurat 4.0 and CellChat were used to cluster and annotate cell subtypes and cellular interaction. U14 (RFP expressed in the nucleus) and macrophage (GFP expressed in cytoplasm and nucleus) were co-cultured to obtain macrophage-tumor fusion cells. In the tumor growth or antibody treatment model, C57BL/6L mice and Nude mice were injected subcutaneously or tail vein with 1*10 6 macrophage-tumor fusion cells or U14 cells, respectively. Statistical analysis was done by a two-sided paired t-test. P 〈 0.05 was considered significant. Results: The HPV- cervical cancer tumor tissue includes 9800 cells with 90% tumor cells and 3% tumor-infiltrating immune cells with immunosuppressive features, similar to a cold tumor microenvironment. Especially, we found a special population of macrophage-tumor fusion cells, which highly expressed the marker genes of macrophages (CD68 and CD163) and of tumor cells (EPCAM and TP63). We confirmed they are not doublets or the endocytosis status of macrophages. ST showed that the macrophage-tumor fusion cells co-localized with tumor cells, macrophages, and also co-localized with T cells, CAFs, and endothelial cells. The NECTIN2/TIGIT was enriched in macrophage-tumor fusion cells to interact with T cells, promoting Treg activation and inhibiting cell proliferation. The LGALS9/HAVCR2 was also enriched in macrophage-tumor fusion cells to interact with macrophage, promoting immunological tolerance. Macrophage-tumor fusion cell hybrids were obtained by in-vitro co-culture of HPV-cervical mouse cell line (U14) and macrophages isolated from GFP transgenic mice. Macrophage-tumor fusion cells obtained higher proliferation and migration abilities than U14 cells in both the immunodeficient and syngeneic mouse tumor models (Ps 〈 0.0001); and higher lung metastasis rate and intensity in the treated tail vein metastasis model (Ps = 0.039). Then we evaluated potential therapeutic targets found on macrophage-tumor fusion cells, identifying blocking TIGIT significantly inhibited the growth of macrophage-tumor fusion tumors in C57/BL6 mouse model, similar to the blocking PD1. Conclusions: This study sheds light on a novel tumor immune escape mechanism of HPV-negative cervical cancer by discovering macrophage-tumor fusion cells, which could provide a potential therapeutic strategy for the clinic.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 4
    In: Cancer Biomarkers, IOS Press, Vol. 34, No. 1 ( 2022-04-18), p. 149-159
    Abstract: BACKGROUND: Lymphopenia during definitive radiotherapy (RT) has been shown to reduce survival in patients with cervical cancer. However, there are few studies on the significance of onset time of lymphopenia during RT in patients with cervical cancer. OBJECTIVE: This study aimed to exam the prognostic significance of early onset of severe lymphopenia (EOSL) during definitive RT in patients with cervical cancer. METHODS: Newly diagnosed cervical cancer patients treated with definitive RT from January 2015 to December 2019 were eligible for this retrospective study. EOSL was defined as first onset of grade 3–4 lymphopenia ⩽ 3 weeks from the start of RT. Mean body dose (MBD) was the mean radiation dose absorbed by the body during the whole course of external beam RT (EBRT) and was directly obtained from the dose volume histogram (DVH) of the EBRT planning. Logistic regression analysis and restricted cubic spline (RCS) models were applied to assess relationships between clinicopathological factors and EOSL. Survival analysis was performed using Kaplan-Meier curves and log-rank test. A COX regression model was developed to predict overall survival (OS). RESULTS: A total of 104 patients were included and 59.6% had EOSL. MBD (P= 0.04), concurrent cisplatin (P= 0.011), and pre-RT absolute lymphocyte count (ALC) (P= 0.001) were associated with EOSL. A linear relationship (P for non-linearity = 0.803) between MBD and risk of EOSL was found. Patients with EOSL had decreased OS (2-yr 75.1% vs 91.1%, P= 0.021) and progression-free survival (PFS) (2-yr 71.2% vs 83.7%, P= 0.071). An OS prediction COX model was developed with C-index of 0.835 and AUC of 0.872. CONCLUSIONS: EOSL during definitive RT correlates with MBD and predicts poor survival in patients with cervical cancer.
    Type of Medium: Online Resource
    ISSN: 1875-8592 , 1574-0153
    Language: Unknown
    Publisher: IOS Press
    Publication Date: 2022
    detail.hit.zdb_id: 2525487-X
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  • 5
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 12 ( 2022-4-28)
    Abstract: Lymphopenia is a known significant factor for treatment outcome in cancer patients, with underlying risk factor poorly understood in breast cancer. We hypothesize that the effective dose to the circulating immune cells (EDIC) which was related with lymphopenia in lung cancer will also have significant effect for radiation induced lymphopenia (RIL) in patients with breast cancer. Material and Methods Patients treated with adjuvant radiotherapy (RT) and with complete blood tests within one week from RT end/start (post/preRT) were eligible in this study. Radiation dosimetric factors were collected retrospectively, and EDIC for each patient was calculated based on the doses to lung, heart and total body according to the model description, as previously reported. RIL was defined by the CTCAE5.0 based on postRT peripheral lymphocyte count (PLC). Linear regression was first used to test the correlation between EDIC with post/preRT PLC ratio and postRT PLC, using all these as continuous variables. Normal tissue complication probability (NTCP) was used to develop models that predict the CTCAE graded RIL from EDIC. Results A total of 735 patients were eligible. The mean post/preRT PLC ratio was 0.66 (95% CI: 0.64-0.68) and mean EDIC of breast cancer was 1.70Gy (95% CI: 1.64-1.75). Both post/preRT PLC ratio and postRT PLC were significantly correlated with EDIC (P & lt;0.001), with R 2 of 0.246. For patients with normal preRT PLC, the post/preRT PLC ratio was better associated with EDIC, and postRT PLC was expressed as PLC preRT × (0.89 – 0.16 × EDIC ). For patients with preRT lymphopenia, postRT PLC was better associated with EDIC and it was 1.1 – 0.17 × EDIC . Using binned EDIC as the dose variable, the bootstrap validated NTCPs fit the data nicely with R 2 of 0.93, 0.96, and 0.94 for grade-1, grade-2, and grade-3 RIL, respectively. The corresponding EDIC to induce 50% of grade-1, grade-2 and grade-3 RIL was 1.2, 2.1 and 3.7 Gy, respectively. Conclusion EDIC is a significant factor for RIL in patients with breast cancer, and may be used to compute the risk of lymphopenia in each individual patient with the use of the conventional NTCP modeling. External validation is needed before the EDIC can be used to guide RT plan.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2649216-7
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e17528-e17528
    Abstract: e17528 Background: Radiotherapy (RT) is the most widely used conventional first-line treatment in cervical cancer (CC). However, the treatment response rate was only 10%-40%, and even lower in HPV- negative CC (HPV- CC). So far, previous knowledge of radiotherapy on tumor and tumor immune microenvironment (TME) remodeling is still insufficient. In this study, we aimed to comprehensively understand the dynamic change of tumor and TME of HPV- CC at the single-cell level. Methods: The single-cell and spatial transcriptome sequencing (STRNAseq) were used to analyze the TME of newly diagnosed HPV- CC tumor tissues, including pre-radiotherapy and 3 weeks after radiotherapy. Tissue samples were split into two parts, the freshly lysed single-cell suspension for 10X single-cell sequencing, and another part that was immediately processed into frozen and embedded for STRNAseq. Cell clustering, annotation and Single-cell sequencing and spatial transcriptome integration were analyzed by Seurat 4.0. The CNV of epithelial cells (ECs) was estimated by InferCNV. Results: A total of 14000 cells were obtained from paired HPV-CC patient samples (pre-RT and 3 weeks after RT) and clustered into 21 cell subsets. Six EC subsets, four fibroblast subsets, three macrophage subsets, two T cell subsets, two B cell subsets, one mast cell cluster, and an endothelial cell cluster were discovered. CNV analysis revealed that all ECs were malignantly proliferating tumor cells. Tumor cells accounted for 90% of the total tumor tissue prior to RT, but only less than 1% of tumor cells remain after RT. Fibroblasts and myeloid cells, which make up 60% of tumor tissue, increase significantly after radiotherapy, with myeloid cells accounting for nearly 50% of the total. Furthermore, we found a population of cells in the Post-RT sample that were both highly expressed CD14 and CD68 (macrophage biomarkers) and highly expressed COL1A2 (fibroblast biomarker). Differential analysis showed that this group of cells was down-regulated in Focal adhesion and ECM-receptor interaction pathways, while up-regulated in cytokine secretion and phagosome pathways, indicating that this group of cells might remodel the intercellular matrix and interacted with other cells to regulate the immune microenvironment. Integrating single-cell and spatial transcriptome data, fibroblasts and myeloid cells formed a tight co-distribution in tissues after radiotherapy, implying that their interaction is critical for the formation of the tumor immune microenvironment. Conclusions: This study comprehensively analyzed the dynamic change of tumor and TME of HPV- CC treated with RT at the single-cell transcriptional scale. After radiotherapy, fibroblasts and myeloid cells significantly increased and were highly heterogeneous, and the interaction between them is critical in forming a tumor ecosystem for radiotherapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e21215-e21215
    Abstract: e21215 Background: Indoleamine 2, 3-dioxygenase (IDO), a known immunoinhibitory enzyme, plays an important role on tumor metastasis through manipulation of host immune status. We have demonstrated that IDO level has prognostic value and low IDO level is associated with low risk of distant metastasis in patients with non-small cell lung cancer (NSCLC). However, the association between IDO immune status in patients with brain metastasis (BrM) is unknown. We hypothesized that the IDO1 activity are different in the NSCLC patients of various stages and in patients with or without BrM and the IDO mRNA expression in brain metastatic lesion differ from the primary tumor or metastasized regional lymph nodes. Methods: This was part of a prospective study of blood immune biomarkers for prognosis and prediction. Newly diagnosed or recurrent NSCLC patients were eligible. Blood samples were obtained before treatment start and plasma were used for the Kynurenine (Kyn) and tryptophan (Trp) measurement by the high-performance chromatography. Kyn and trp was detected with more than 95% re-productivity. IDO activity was defined as ratio of kyn/Trp. Student T-test and One-way anova were applied for group comparison. CI: confidence interval. P 〈 0.05 was considered as statistical significance. The IDO cellular expression was analyzed by the http://ureca-singlecell.kr/ website tool using the GEO dataset GSE131907. Results: Between July 2019 and Dec 2020, a total of 121 patients with NSCLC were eligible. The mean concentration of Kyn was 1.69 uM in patients with stage IV (n = 60, CI: 1.38-2.00), compared with 1.57 in patients with stage I (n = 38, CI: 1.03-2.10), 1.63 in stage II (n = 13, CI: 1.03-2.23) and 2.01 in stage III (n = 10, CI: 0.72-3.30, mean = 2.01). The mean ratio of Kyn:Trp was 0.10 in stage IV (n = 60, CI: 0.07-0.12), compared with 0.13 in patients with stage I (n = 38, CI: 0.06-0.20), 0.15 in stage II (n = 13, CI: 0.03-0.29) and 0.15 in stage III (n = 10, CI: 0.12-0.29). In patients with stage IV, there was no significant difference in the kyn concentration in patients with BrM (n = 13) and those without BrM (n = 47) (mean: 1.74, CI: 0.47-2.41 v.s 2.03 mean: 1.12-3.08; p = 0.45). The IDO activity in the patients with BrM was not significantly different from that of patients without BrM (mean: 0.11, CI: 0.03-0.20 v.s mean: 0.13, CI: 0.08-0.17; p = 0.74). Interestingly, GEO dataset analysis of the IDO1 mRNA expressions in 44 patients showed enrichments in myeloid cells in primary lung cancer tumor, natural killer cells in metastasized lymph nodes, and B cells in brain metastatic lesion. Conclusions: This study demonstrated no significant differences in circulating IDO expressions in patients with brain metastasis but differential IDO patterns of cellular expression in brain metastasis from that of primary tumor in NSCLC patients. This finding suggests the need of new strategy of research for immune status in the brain metastatic process of non-small cell lung cancer.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 8
    In: Molecular and Clinical Oncology, Spandidos Publications, Vol. 15, No. 6 ( 2021-10-15)
    Type of Medium: Online Resource
    ISSN: 2049-9450 , 2049-9469
    Language: Unknown
    Publisher: Spandidos Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2796865-0
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