Immunofluorescence-Detected Infiltration of CD4+FOXP3+ Regulatory T Cells is Relevant to the Prognosis of Patients With Endometrial Cancer

ObjectiveHost antitumor immune responses are associated with many types of immune cells and soluble components. In particular, CD8+ cytotoxic T lymphocytes (CTLs) play a central role. Regulatory T cells (Tregs) have been reported to induce tumor immune tolerance in various cancers. In the present study, we evaluated lymphocytic infiltration in endometrial cancer tissue to clarify its relationship with clinicopathological factors and the prognosis of patients.MethodsThe study included 53 patients whose condition was diagnosed as endometrial cancer between 1994 and 2004 at Keio University hospital. Using formalin-fixed, paraffin-embedded specimens of the uterus, immunohistochemistry was performed with antihuman CD8, antihuman CD4, and antihuman FOXP3 primary antibodies, and the binding sites of the antibodies were visualized using fluorescence-conjugate secondary antibodies. CD4+FOXP3+ cells were identified as Tregs in this study. The numbers of CD8+ cells, CD4+ cells, and Tregs as well as the Treg/CD8+ and Treg/CD4+ ratios were analyzed to evaluate the relationship between clinicopathological factors and patient prognosis.ResultsOf the 53 patients studied, 50.9% of them had early-stage disease, 49.1% had advanced stage disease, 47.2% had well-differentiated cancer (grade [G] 1), 24.5% had moderately differentiated cancer (G2), and 28.3% had poorly differentiated cancer (G3). The CD8+ and CD4+ cell counts, Treg count, and Treg/CD8+ and Treg/CD4+ ratios were significantly higher in the patients with advanced poorly differentiated carcinomas and with positive lymphovascular space invasion than in those with early well-differentiated carcinomas and with negative lymphovascular space invasion. In disease-free survival, the prognosis of the patients with high Treg counts and Treg/CD8+ ratios was significantly worse than that of the patients with low Treg counts and Treg/CD8+ ratios (P < 0.05).ConclusionsThe Treg count and Treg/CD8+ ratio may be new prognostic factors for endometrial cancer.

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752 The impact of grade of differentiation and BRAF mutation status on neoantigen and immune landscape in papillary thyroid cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0752 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A800-A800

Author(s):

Myungwoo Nam ◽

Woojung Yang ◽

Ju Young Lee ◽

Jaeyoun Choi ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Braf Mutation ◽

Cytolytic Activity ◽

Activity Score ◽

Cyt B ◽

Mutation Status ◽

Poorly Differentiated ◽

Immune Traits ◽

Well Differentiated

BackgroundThe use of immune checkpoint inhibitors (ICIs) in cancer treatment has been approved by the FDA, but its application is experimental in the treatment of papillary thyroid cancer (PTC). Induction of immune response via recognition of neoantigens is considered to be the basis for the treatment mechanism of ICIs.1 However, the neoantigen landscape has not been explored in PTC. Our aim is to investigate the immune landscape of PTC in relation to neoantigens, taking into account the BRAF mutation status and grade of differentiation as contributing factors.MethodsBRAF V600E mutation status and thyroid differentiation scores (TDSs) were gathered from the PTC cohort of The Cancer Genome Atlas (TCGA). TDS was derived from the mRNA expression levels of 16 thyroid function genes to quantify the grade of differentiation. Tumors with TDSs in the 1st quartile and 4th quartile were defined as poorly differentiated and well differentiated, respectively. The neoantigen burden for each sample was predicted using CloudNeo pipeline. The infiltration of immune cells was calculated through CIBERSORT.ResultsAmong 400 patients with predicted neoantigen data, 187 (47%) had BRAF mutations. The BRAF mutated tumors showed increased cytolytic activity score (CYT, p=0.001), increased infiltration of regulatory T cells (Treg, p<0.001), and higher PD-L1 expression (p<0.001) compared to BRAF wild-type tumors (figure 1). In regard to grade of differentiation, poorly differentiated tumors showed increased CYT (p=0.002), increased infiltration of Treg (p<0.001), and higher PD-L1 expression (p<0.001) compared to well differentiated tumors (figure 2). However, BRAF mutation status or grade of differentiation did not correlate with the neoantigen burden. Also, the neoantigen burden did not show any correlations with immune landscape features such as infiltration of CD8+ T cells or Treg, CYT, and PD-L1 expression.Abstract 752 Figure 1Immune traits according to BRAF mutation status. (a) Cytolytic activity score(CYT). (b) Infiltration of regulatory T cells(Tregs). (c) PD-L1 expression.Abstract 752 Figure 2Immune traits according to grade of differentiation. (a) Cytolytic activity score(CYT). (b) Infiltration of regulatory T cells(Tregs). (c) PD-L1 expression.ConclusionsIncreased CYT and higher expression of PD-L1 in the BRAF mutated or the poorly differentiated tumors imply the possible role of ICI use in these subgroups of patients. However, the immune response to these subgroups does not seem to be mediated through the increase in neoantigen formation. Further studies are warranted to explore markers for immunotherapy implication.ReferencesSchumacher TN, Schreiber RD, Neoantigens in cancer immunotherapy. Science 2015; 348:69–74.

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Usefulness of peripheral regulatory T-cells induced by Notch signaling pathway-driven indoleamine 2, 3-dioxygenase positive dendritic cell as a biomarker for the decision for IPMN surgical indications.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.181 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 181-181

Author(s):

Tetsuya Ikemoto ◽

Mitsuo Shimada ◽

Toru Utsunomiya ◽

Yuji Morine ◽

Satoru Imura ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Notch Signaling ◽

Signaling Pathway ◽

Peripheral Blood ◽

Notch Signaling Pathway ◽

Clinicopathological Factors ◽

Surgical Indications ◽

Intracellular Domain ◽

Indoleamine 2

181 Background: This study was performed to elucidate the expression of the Notch signaling pathway regulated by dendetric cell (DC) and their correlations to clinicopathological factors of intraductal papillary mucinous neoplasms (IPMNs) as a new biomarker for surgical indications. We already reported that regulatory T cells (Tregs) play an important role in tumor immunity (Pancreas 2006, ASCO-GI 2009), however, the whole mechanism of control of peripheral Tregs remains unclear. It is reported that Indoleamine 2, 3-dioxygenase (IDO) induces active Treg from naïve CD4+Tcells through dendritic cells. Otherwise, we also reported that the Notch signaling pathway is involved in tumor growth and DC function (JI 2010). Thus we focused that Indoleamine 2,3-deoxygenase(IDO)-Treg axis driven by Notch signaling in IPMNs. Methods: Peripheral blood samples and resected specimens from 20 patients with IPMN were evaluated. All patients were pathologically diagnosed with IPMN. Resected specimens were immunohistochemically evaluated (anti-Notch1, anti-Notch2, anti-Notch2-intracellular domain and anti-IDO antibody staining) and compared to clinicopathological factors. Peripheral Treg populations were analyzed with an automated flow cytometer. Results: Disease-free survival was significantly worse in the Notch1 high-expression group (P<0.05). Notch2 family expressions were higher in intraductal papillary mucinous carcinoma (IPMC) than in intraductal papillary mucinous adenoma (IPMA) (Notch2, P< 0.05; Notch2-intracellular domain, P < 0.05). Jagged1 and IDO expressions were significantly higher in IPMC than in IPMA (P < 0.05) and was significantly related to recurrence. The Treg population in peripheral blood was higher in patients with IPMC than in those with IPMA (P < 0.01). Conclusions: Notch signaling, especially Jagged1 expression, regulated by IDO+DC reflects IPMN aggressiveness. Our data strongly suggest that peripheral Treg induced by Notch signaling pathway driven IDO+DC may be a nobel biomarker for the decision for IPMN surgical indications.

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Suppressive activity of regulatory T cells correlates with high CD4+ T-cell counts and low T-cell activation during chronic simian immunodeficiency virus infection

AIDS ◽

10.1097/qad.0b013e3283437c7b ◽

2011 ◽

Vol 25 (5) ◽

pp. 585-593 ◽

Cited By ~ 6

Author(s):

Ingrid Karlsson ◽

Benoît Malleret ◽

Patricia Brochard ◽

Benoît Delache ◽

Julien Calvo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Infection ◽

Regulatory T Cells ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Suppressive Activity ◽

Cell Counts ◽

Immunodeficiency Virus

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Diverse clinical outcome and predictors for clinical outcome in patients with HCC treated with TACE.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.442 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 442-442

Author(s):

Prarthna Bhardwaj ◽

Petra Prins ◽

Alexander Y. Kim ◽

Rheena Jha ◽

Hongkun Wang ◽

...

Keyword(s):

Clinical Outcome ◽

Progression Free Survival ◽

Rank Test ◽

T Stage ◽

Kaplan Meier ◽

Stage Disease ◽

T4 Stage ◽

Poorly Differentiated ◽

Well Differentiated ◽

Tace Treatment

442 Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer, and the second leading cause of cancer-related death, worldwide. This reflects the challenges facing HCC treatment. Methods: Patients (pts) with HCC receiving TACE treatment (n = 96) were examined retrospectively for clinical outcome and its possible predictors. The number of TACE treatments and the time elapsed between each treatment were assessed and correlated with overall survival (OS) using the log rank test of Kaplan Meier curves. T-stage, level of differentiation, vascular invasion, and Child Pugh score at the time of HCC diagnosis were compared among pts who received different numbers of TACE treatments (Kaplan-Meier survival analysis, ANOVA and student T test). Results: TACE treated pts had a median OS of 46 month (mo) and progression free survival of 12 mo (difference in time between the date of first progression and the date of diagnosis). Pts received 1-2 (n = 52), 3-4 (n = 28), or 5-6 (n = 16) TACE treatments. We found that pts who had only 1-2 TACE treatments had significantly shorter median OS (38 mo) than those who received 3-4 or 5-6 treatments (48 and 83 mo; p < 0.05). Of the 96 pts studied 22, 33, 37, and 3 pts had T1, T2- T3 and T4-stage HCC, respectively. Only 39 pt tumors underwent pathological analysis, and 13 were well-differentiated (WD), while 24 were moderately- or poorly- differentiated (MPD) (p > 0.05). Tumor T-stage and differentiation were correlated with the number of TACE treatments received. Thus, 30% of pts (n = 10) with T2-stage disease compared with 10% (n = 4) with T3-stage disease received 5-6 TACE treatments (p < 0.001). Similarly, 30% of WD cases (n = 4) compared with only 8% of MPD cases (n = 2) received 5-6 TACE treatments (p < 0.001). The duration between the second and third TACE treatments ( < 4 mo, 5-8 mo or > 8 mo) seemed to correlate with outcome (p < 0.05). Conclusions: Pt survival time following TACE treatment is diverse and correlates with the number of TACE treatments. Pts with T3-stage, or MPD HCC tended to receive fewer TACE treatments than those with T2-stage or WD HCC, and have worse outcomes. Other therapies should certainly be considered for pts with T3-stage and/or MPD tumors.

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Clinical features and prognosis of patients with liposarcoma: Single-center experience.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e22557 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e22557-e22557

Author(s):

Metin Demir ◽

Deniz Can Guven ◽

Burak Yasin Aktas ◽

Gürkan Güner ◽

Oktay Halit Aktepe ◽

...

Keyword(s):

Clinical Features ◽

Early Stage ◽

Early Stage Disease ◽

Single Center Experience ◽

Kaplan Meier ◽

Stage Disease ◽

Node Positive Disease ◽

Well Differentiated ◽

Pleomorphic Liposarcomas

e22557 Background: Liposarcomas constitute 15% of all soft tissue sarcomas.They consist of four subtypes;well-differentiated,dedifferentiated,myxoid and pleomorphic.In this trial we assessed demographic and clinical features of patients with liposarcoma who were treated in our hospital.Methods: Patients who were diagnosed with liposarcoma in Hacettepe University Medical Oncology Department between 2005and2015(n = 119) were included. Patients’ data were collected from hospital registration system.Survival analyses were performed with Kaplan Meier analyses.Results: At the time of diagnosis, the vast majority of patients had localized and/or node positive disease(n = 98),8 patients had metastatic disease.Further analyses hold for only early stage disease:Median age was 52(min:18-max:81).105 patients(94.6%) had upfront surgery.26(23.4%) and 30 patients(27%) received perioperative chemotherapy(CT) and radiotherapy(RT),respectively.The most commonly used CT agents were ifosfamide, anthracyclines, etoposide,taxanes and gemcitabine.At a median follow-up of 45months, relapses were observed in 34 patients(30.6%) and 35 patients(31.5%) died.Median overall survival(OS) was 113.1 months and median relapse free survival (RFS) was 23.8 months.Perioperative CT and RT were not associated with improved RFS and OS.Among patients with early stage disease; median RFS of patients with well-differentiated, dedifferentiated, myxoid and pleomorphic subtypes were 31.8,34.3,28 and 5.2months,respectively(p = 0.013).Well-differentiated group had significantly higher RFS than those with pleomorphic liposarcomas(p = 0.003).The mostly used CT drugs in recurrent setting were ifosfamide+doxorubicine(42.9%) and ifosfamide+etoposide(21.4%).Conclusions: Liposarcoma prognosis varies significantly with histological subtype and the efficacy of systemic chemotherapy is limited both in early stage and advanced disease.[Table: see text]

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Therapeutic Targets and Opportunities in Endometrial Cancer: Update on Endocrine Therapy and Nonimmunotherapy Targeted Options

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_280495 ◽

2020 ◽

pp. 245-255

Author(s):

Helen J. MacKay ◽

Victor Rodriguez Freixinos ◽

Gini F. Fleming

Keyword(s):

Endometrial Cancer ◽

Endocrine Therapy ◽

Metastatic Disease ◽

Early Stage ◽

Treatment Options ◽

Treatment Strategies ◽

Targeted Treatment ◽

Early Stage Disease ◽

New Era ◽

Stage Disease

Worldwide, the incidence of endometrial cancer is increasing. Although the prognosis remains good for patients diagnosed with early-stage disease, for those diagnosed with recurrent or metastatic disease, options have been limited, and prognosis is short. Optimizing and identifying new well-tolerated treatments for women living with endometrial cancer is a top priority. A new era is dawning where we are starting to see the integration of clinically relevant genomic and pathologic data to inform and refine treatment strategies for women with endometrial cancer. Here, we focus on reviewing nonimmunotherapy-based targeted treatment options and emerging directions for women with endometrial cancer.

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Effects of Quorum Sensing Systems on Regulatory T Cells in Catheter-RelatedPseudomonas aeruginosaBiofilm Infection Rat Models

Mediators of Inflammation ◽

10.1155/2016/4012912 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Lei Feng ◽

Qingqing Xiang ◽

Qing Ai ◽

Zhengli Wang ◽

Yunhui Zhang ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

T Cells ◽

Immune System ◽

Regulatory T Cells ◽

Total Cell ◽

Bacterial Clearance ◽

Pathological Changes ◽

Rat Models ◽

Cell Counts ◽

Biofilm Infection

Background. Quorum sensing (QS) systems play an important role in modulating biofilm formation. Recent studies have found that the QS molecules had complex effects on the host immune systems. In addition, regulatory T cells (Tregs), known as important negative regulators in the immune system, have been found upregulated in multiple chronic infections. Therefore, the QS systems were hypothesized to be involved in modulating Tregs in biofilm-associated infections.Object. To explore the effects of QS systems on Tregs in catheter-relatedPseudomonas aeruginosabiofilm infection rat models.Method. Catheter-relatedPseudomonas aeruginosabiofilm infection rat models were established; the bacterial clearance rates, total cell counts in bronchoalveolar lavage (BAL) fluid, pathological changes of lungs, and the levels of Foxp3, TGF-β1, and IL-10 in PAO1 strain group were examined and compared with the QS-mutant ΔlasRΔrhlRandΔlasIΔrhlIgroups.Results. In PAO1 group, the bacterial clearance rates were lower, total cell counts were higher, pathological changes were severer, and the levels of Foxp3, TGF-β1, and IL-10 were significantly higher compared with QS-mutant groups(p<0.05). No significant difference was observed between the two QS-mutant groups(p>0.05).Conclusion. QS systems can trigger host immune system, accompanied with the upregulation of Tregs.

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Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma

Blood ◽

10.1182/blood-2003-04-1044 ◽

2003 ◽

Vol 102 (12) ◽

pp. 4059-4066 ◽

Cited By ~ 118

Author(s):

Nikhil Yawalkar ◽

Katalin Ferenczi ◽

David A. Jones ◽

Keiichi Yamanaka ◽

Ki-Young Suh ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lymphoma ◽

Early Stage ◽

Cell Repertoire ◽

Early Stage Disease ◽

Stage Disease ◽

Beta Variable ◽

Disease Stages ◽

Complementarity Determining Region

Abstract Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T cells. A major feature of CTCL is profound immunosuppression, such that patients with advanced mycosis fungoides or Sézary syndrome have been compared with patients with advanced HIV disease and are susceptible to opportunistic infection. The etiology of this immunosuppression is unclear. We analyzed peripheral blood T cells of patients with CTCL with stage I to IV disease, using a sensitive beta-variable complementarity-determining region 3 spectratyping approach. Our data revealed a profound disruption of the complexity of the T-cell repertoire, which was universally observed in patients with advanced disease (stages III and IV), and present in up to 50% of patients with early-stage disease (stages I and II). In most patients, multiple monoclonal and oligoclonal complementarity-determining region 3 (CDR3) spectratype patterns in many different beta-variable families were seen. Equally striking was a reduction of normal T cells (as judged by absolute CD4 counts) across multiple beta-variable families. In general, CTCL spectratypes were reminiscent of advanced HIV spectratypes published elsewhere. Taken together, these data are most consistent with a global assault on the T-cell repertoire in patients with CTCL, a process that can be observed even in early-stage disease. (Blood. 2003;102:4059-4066)

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