scholarly journals Immune phenotype of patients with stage IV metastatic inflammatory breast cancer

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Sandra V. Fernandez ◽  
Alexander W. MacFarlane ◽  
Mowafaq Jillab ◽  
Maria F. Arisi ◽  
Jennifer Yearley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Nk Cells ◽  
Inflammatory Breast Cancer ◽  
Peripheral Blood ◽  
Stage Iv ◽  
Effector Memory ◽  
Immune Parameters ◽  
Cytolytic Granule ◽  
Tumor Biopsies

Abstract Background Inflammatory breast cancer (IBC) is a rare but aggressive carcinoma characterized by severe erythema and edema of the breast, with many patients presenting in advanced metastatic disease. The “inflammatory” nature is not due to classic immune-mediated inflammation, but instead results from tumor-mediated blockage of dermal lymphatic ducts. Previous work has shown that expression of PD-L1 on tumor cells can suppress T cell activation in triple-negative (TN) non-IBC breast cancer. In the present work, we investigated immune parameters in peripheral blood of metastatic IBC patients to determine whether cellular components of the immune system are altered, thereby contributing to pathogenesis of the disease. These immune parameters were also compared to PD-1 and PD-L1 expression in IBC tumor biopsies. Methods Flow cytometry-based immune phenotyping was performed using fresh peripheral blood from 14 stage IV IBC patients and compared to 11 healthy age-similar control women. Immunohistochemistry for CD20, CD3, PD-1, and PD-L1 was performed on tumor biopsies of these metastatic IBC patients. Results IBC patients with Stage IV disease had lymphopenia with significant reductions in circulating T, B, and NK cells. Reductions were observed in all subsets of CD4+ T cells, whereas reductions in CD8+ T cells were more concentrated in memory subsets. Immature cytokine-producing CD56bright NK cells expressed higher levels of FcγRIIIa and cytolytic granule components, suggesting accelerated maturation to cytolytic CD56dim cells. Immunohistochemical analysis of tumor biopsies demonstrated moderate to high expression of PD-1 in 18.2% of patients and of PD-L1 in 36.4% of patients. Interestingly, a positive correlation was observed between co-expression levels of PD-L1 and PD-1 in tumor biopsies, and higher expression of PD-L1 in tumor biopsies correlated with higher expression of cytolytic granule components in blood CD4+ T cells and CD56dim NK cells, and higher numbers of CD8+ effector memory T cells in peripheral blood. PD-1 expression in tumor also correlated with increased infiltration of CD20+ B cells in the tumor. Conclusions Our results suggest that while lymphocyte populations are severely compromised in stage IV IBC patients, an immune response toward the tumor had occurred in some patients, providing biological rationale to evaluate PD-1/PD-L1 immunotherapies for IBC.

scholarly journals Interleukin-15 Increases Effector Memory CD8+ T Cells and NK Cells in Simian Immunodeficiency Virus-Infected Macaques

2005 ◽  
Vol 79 (8) ◽  
pp. 4877-4885 ◽  
Author(s):  
Yvonne M. Mueller ◽  
Constantinos Petrovas ◽  
Paul M. Bojczuk ◽  
Ioannis D. Dimitriou ◽  
Brigitte Beer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Low Dose ◽  
Effector Memory ◽  
High Dose ◽  
Immunodeficiency Virus ◽  
Interleukin 15

ABSTRACT Interleukin-15 (IL-15) in vitro treatment of peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus (HIV)-infected individuals specifically enhances the function and survival of HIV-specific CD8+ T cells, while in vivo IL-15 treatment of mice preferentially expands memory CD8+ T cells. In this study, we investigated the in vivo effect of IL-15 treatment in 9 SIVmac251-infected cynomolgus macaques (low dose of IL-15, 10 μg/kg of body weight, n = 3; high dose of IL-15, 100 μg/kg, n = 3; control [saline], n = 3; dose administered twice weekly for 4 weeks). IL-15 treatment induced a nearly threefold increase in peripheral blood CD8+CD3− NK cells. Furthermore, CD8+ T-cell numbers increased more than twofold, mainly due to an increase in the CD45RA−CD62L− and CD45RA+CD62L− effector memory CD8+ T cells. Expression of Ki-67 in the CD8+ T cells indicated expansion of CD8+ T cells and not redistribution. IL-15 did not affect CD4+ T-cell, B-cell, and CD14+ macrophage numbers. No statistically significant differences in changes from baseline in the viral load were observed when control-, low-dose-, and high-dose-treated animals were compared. No clinical adverse effects were observed in any of the animals studied. The selective expansion of effector memory CD8+ T cells and NK cells by IL-15 further supports IL-15's possible therapeutic use in viral infections such as HIV infection.

scholarly journals Reduced Immunosenescence of Peripheral Blood T Cells in Parkinson’s Disease with CMV Infection Background

2021 ◽  
Vol 22 (23) ◽  
pp. 13119
Author(s):  
Julia D. Vavilova ◽  
Anna A. Boyko ◽  
Natalya V. Ponomareva ◽  
Vitaly F. Fokin ◽  
Ekaterina Y. Fedotova ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Chronic Inflammation ◽  
Peripheral Blood ◽  
Effector Memory ◽  
Cmv Infection ◽  
Healthy Donors

Immunosenescence is a process of remodeling the immune system under the influence of chronic inflammation during aging. Parkinson’s disease (PD) is a common age-associated neurodegenerative disorder and is frequently accompanied by neuroinflammation. On the other hand, cytomegalovirus (CMV), one of the most spread infections in humans, may induce chronic inflammation which contributes to immunosenescence, differentiation and the inflation of T cells and NK cells. Currently, there is no clear understanding of immunosenescence severity in PD patients infected with CMV. In this study, we analyzed differentiation stages and immunosenescence characteristics of T cells and NK cells in 31 patients with mild and moderate PD severity, 33 age-matched and 30 young healthy donors. The PD patients were 100% CMV-seropositive compared to 76% age-matched and 73% young CMV-infected healthy donors. The proportion of effector memory T cells re-expressing CD45RA, CD57+CD56− T cells and CD57+CD56+ T cells was significantly reduced in PD patients compared with CMV-seropositive age-matched healthy individuals. The CD57+CD56− T cell proportion in PD patients was similar to that of CMV-seropositive young healthy donors. Thus, PD is characterized by reduced peripheral blood T cell immunosenescence, even against the background of CMV infection.

Immune and molecular determinants of response to neoadjuvant chemotherapy in inflammatory breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11501-11501 ◽  
Author(s):  
Sangeetha Meda Reddy ◽  
Jennifer Ann Wargo ◽  
Alexandre Reuben ◽  
Michael T. Tetzlaff ◽  
Jason Roszik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Neoadjuvant Chemotherapy ◽  
Inflammatory Breast Cancer ◽  
Tissue Bank ◽  
Stage Iv ◽  
Stage Iii ◽  
Response To Treatment ◽  
Receptor Status

11501 Background: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer and has poor responses to standard of care neoadjuvant chemotherapy (NAC). Given there is a limited understanding of the immune microenvironment of IBC, this study aims to characterize the immune and molecular profiles of stage III and IV IBC and to identify biomarkers of response to treatment and targets for future therapies. Methods: IBC patients with available pre-treatment tumor samples and with intent to take to mastectomy were identified in the IBC tumor registry and tissue bank. Tumor infiltrating lymphocyte (TIL) infiltration in the tumor stroma was quantified on H&E slides per consensus guidelines (n = 91). On a subset of patients with available samples, deeper immune profiling was performed, including quantification of CD8 T cells by immunohistochemistry (IHC) (n = 33), PD-L1 tumor expression by IHC (n = 14), myeloid cells by multiplex IHC (n = 15), T cell clonality by T cell receptor sequencing (n = 22), and total mutational load (TML) by whole exome sequencing (n = 20). Results: Mean TIL were higher in tumors from patients that achieved a pathological complete response (pCR) to NAC than from those that did not (13.79 vs 7.24%, p = 0.019) and in patients with stage III compared to stage IV disease (11.90 vs 4.79%, p < 0.001). Though no statistically significant differences in CD8 infiltrate by response, stage, or receptor status were seen, the presence of a more clonal T cell population was predictive of pCR (13.27 vs 5.70% top 5 clone frequency, p = 0.042 among stage III patients). Myeloid cell staining revealed that tryptase staining, indicative of mast cells, was inversely associated with pCR (28.26 vs 108.0 counts/mm2, p = 0.011). Three of fourteen patient tumors displayed low PD-L1 tumor positivity (range 1-2%, 1+-2+) with the others being negative. Genomic profiling showed no statistically significant differences in TML by stage, receptor status, response, or immune infiltrate. Conclusions: Higher TIL, more clonal T cells, and lower mast cell infiltration are predictive of response to NAC in IBC. Comprehensive immune characterization of a larger cohort of pre- and post-treatment samples is currently underway.

Treatment with pembrolizumab in combination with the oncolytic virus pelareorep promotes anti-tumor immunity in patients with advanced pancreatic adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4144-4144
Author(s):  
Devalingam Mahalingam ◽  
Siqi Chen ◽  
Ping Xie ◽  
Aparna Kalyan ◽  
Sheetal Mehta Kircher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Tumor Tissue ◽  
Tumor Response ◽  
Effector Memory ◽  
Epigenetic Mark ◽  
Immunological Changes ◽  
Tumor Biopsies

4144 Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). In prior studies, tumor tissue analysis from patients treated with pelareorep shows pelareorep replication, increased T cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab in patients with PDAC would lead to improved responses and anti-tumor immunological changes within peripheral blood and tumor biopsies in responding patients. Methods: PDAC patients who progressed after first-line treatment received pelareorep at a dose of 4.5x1010 TCID50 IV on Days 1, 2, 3 & 8 of Cycle (C) 1, and Days 1 & 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. The primary objective was overall response rate by RECIST v 1.1 criteria. Secondary objectives included evaluating immunological changes within tumor tissue and peripheral blood, performed by multi-plex immunohistochemistry and spectral flow cytometry (Cytek), respectively. Results: Thirteen patients were enrolled. Disease control was achieved in 33% of the 12 efficacy-evaluable patients. One patient achieved a partial response (PR). Three additional patients achieved stable disease (SD). On-treatment tumor biopsies, collected during C1, showed pelareorep replication, increased infiltration of CD8+ T cells and PD-L1+ cells, and decreased expression of VDAC1, a mitochondrial gatekeeper for tumor promotion, relative to archival tissue. Reduced infiltration of Foxp3+ regulatory T cells (Treg) was observed in patients showing tumor response. Peripheral blood was collected at day 1 of each cycle and on C1 day 8. Relative to pretreatment samples, the number of CD8+ effector memory T cells and B cells tend to increase while the number of Treg cells declined in C2 onwards in patients with tumor response. Furthermore, these patients had increased expression of the mitochondrial protein TOMM20 in CD8+ T cells and decreased expression of PD-1 and the H3K27me3 epigenetic mark in Treg. Treatment was well tolerated with most treatment-related adverse events, including flu-like symptoms, being grade 1 or 2. Conclusions: The combination of pelareorep and pembrolizumab showed a manageable safety profile and modest efficacy in an unselected PDAC population. Additional correlation analyses between treatment efficacy and immunological changes will be presented. The anti-tumor activity of pelareorep and checkpoint blockade therapy is being evaluated further in additional ongoing studies. Clinical trial information: NCT03723915.

CHAPTER 9: Immunology of TBEV-Infections

2020 ◽  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Sample Collection ◽  
Tick Borne Encephalitis ◽  
Viral Infectious Disease ◽  
The Central Nervous System

Tick-borne encephalitis (TBE) is a viral infectious disease of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is usually a biphasic disease and in humans the virus can only be detected during the first (unspecific) phase of the disease. Pathogenesis of TBE is not well understood, but both direct viral effects and immune-mediated tissue damage of the central nervous system may contribute to the natural course of TBE. The effect of TBEV on the innate immune system has mainly been studied in vitro and in mouse models. Characterization of human immune responses to TBEV is primarily conducted in peripheral blood and cerebrospinal fluid, due to the inaccessibility of brain tissue for sample collection. Natural killer (NK) cells and T cells are activated during the second (meningo-encephalitic) phase of TBE. The potential involvement of other cell types has not been examined to date. Immune cells from peripheral blood, in particular neutrophils, T cells, B cells and NK cells, infiltrate into the cerebrospinal fluid of TBE patients.

scholarly journals Erratum to: Content of HLA-G+ T Cells in the Peripheral Blood from Healthy Women and Breast Cancer Patients

2016 ◽  
Vol 160 (4) ◽  
pp. 592-592
Author(s):  
E. O. Ostapchuk ◽  
Yu. V. Perfil’eva ◽  
Sh. Zh. Talaeva ◽  
N. A. Omarbaeva ◽  
N. N. Belyaev
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Breast Cancer Patients ◽  
Healthy Women

scholarly journals IL6 Signaling in Peripheral Blood T Cells Predicts Clinical Outcome in Breast Cancer

2016 ◽  
Vol 77 (5) ◽  
pp. 1119-1126 ◽  
Author(s):  
Lei Wang ◽  
Andrea K. Miyahira ◽  
Diana L. Simons ◽  
Xuyang Lu ◽  
Andrew Y. Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Clinical Outcome ◽  
Peripheral Blood

Chapter 9: Immunology of TBEV-Infection

2021 ◽  
Author(s):  
Sara Gredmark-Russ ◽  
Renata Varnaite
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Sample Collection ◽  
Tick Borne Encephalitis ◽  
Viral Infectious Disease ◽  
The Central Nervous System

Tick-borne encephalitis (TBE) is a viral infectious disease of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is usually a biphasic disease and in humans the virus can only be detected during the first (unspecific) phase of the disease. Pathogenesis of TBE is not well understood, but both direct viral effects and immune-mediated tissue damage of the central nervous system may contribute to the natural course of TBE. The effect of TBEV on the innate immune system has mainly been studied in vitro and in mouse models. Characterization of human immune responses to TBEV is primarily conducted in peripheral blood and cerebrospinal fluid, due to the inaccessibility of brain tissue for sample collection. Natural killer (NK) cells and T cells are activated during the second (meningo-encephalitic) phase of TBE. The potential involvement of other cell types has not been examined to date. Immune cells from peripheral blood, in particular neutrophils, T cells, B cells and NK cells, infiltrate into the cerebrospinal fluid of TBE patients.

scholarly journals Role of CD4+ CD25+ FOXP3+ regulatory T-cells and human papilloma virus infection in Egyptian Women with breast cancer

2019 ◽  
Author(s):  
Amany Tawfeik ◽  
Ahmed Mora ◽  
Ahmed Osman ◽  
Nabila Elsheikh ◽  
Mohamed Elrefaei
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
High Risk ◽  
Human Papilloma Virus ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Early Stage ◽  
Significant Proportion ◽  
Papilloma Virus ◽  
Egyptian Women

Abstract Several subsets of regulatory CD4+ T cells (CD4+ Tregs) have been described in peripheral blood and tumor microenvironment and blood of breast cancer (BC) patients and may play a key role in the progression of BC. High-risk human papilloma virus (HPV) have a causal role in a significant proportion of cervical, and head, and neck tumors and may play an important role in evoking neoplasia in BC. In this study we assessed the prevalence of CD4+Tregs (CD4+CD25+ FOXP3+ cells) and CD8+T cells by flow cytometry in peripheral blood from a total of 55 Egyptian women, including 20 treatment-naïve BC, 15 with breast benign lesions (BBL) and 20 healthy volunteers (HV). High-risk HPV genotype type 16, 18, and 31 was investigated in breast tissue from all BC and BBL patients using Real-Time PCR. HPV was detected in 4 BC, but in none of BBL patients. The frequency of CD4+ Tregs was significantly higher in BC compared to BBL and HV, (p < 0.001). In addition, we observed a significantly higher frequency of CD8+ T cells in peripheral blood of patients with late stage III compared to early stage I and II BC (p = 0.011). However, there was no significant association between the ratio of CD8+ T cell to CD4+ Tregs frequencies and the expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). In conclusion, CD4+ Tregs may contribute to progression BC in Egyptian women with HPV infection. The potential role CD4+ Tregs as a prognostic or predictive parameter should be analyzed in a larger longitudinal study with sufficient follow-up time.

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