scholarly journals Association of Germline Variants in Natural Killer Cells With Tumor Immune Microenvironment Subtypes, Tumor-Infiltrating Lymphocytes, Immunotherapy Response, Clinical Outcomes, and Cancer Risk

2019 ◽  
Vol 2 (9) ◽  
pp. e199292 ◽  
Author(s):  
Xue Xu ◽  
Jianqiang Li ◽  
Jinfeng Zou ◽  
Xiaowen Feng ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Cancer Risk ◽  
Natural Killer ◽  
Clinical Outcomes ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Microenvironment ◽  
Killer Cells ◽  
Germline Variants ◽  
Tumor Immune Microenvironment ◽  
Infiltrating Lymphocytes

scholarly journals Plasma HSP90AA1 Predicts the Risk of Breast Cancer Onset and Distant Metastasis

2021 ◽  
Vol 9 ◽  
Author(s):  
Haizhou Liu ◽  
Zihan Zhang ◽  
Yi Huang ◽  
Wene Wei ◽  
Shufang Ning ◽  
...  
Keyword(s):  
Breast Cancer ◽  
B Cells ◽  
Natural Killer Cells ◽  
Cancer Risk ◽  
Natural Killer ◽  
Carbohydrate Antigen ◽  
Monocyte Count ◽  
Poor Overall Survival ◽  
Killer Cells ◽  
D Dimer

AimWe aimed to develop and validate a comprehensive nomogram containing pre-treatment plasma HSP90AA1 to predict the risk of breast cancer onset and metastasis.MethodsWe assessed the expression of HSP90s in breast cancer patients using an online database. To verify the results, 677 patients diagnosed with breast cancer and 146 patients with benign breast disease between 2014 and 2019 were selected from our hospital and were divided into cancer risk and metastasis risk cohorts. We focused on HSP90AA1 to elucidate the risks of onset and metastasis in the cohorts.ResultsExpression levels of HSP90AA1, HSP90AA2, HSP90AB1, HSP90B1, and TRAP1 were linked to disease progression. Survival analysis using the GEPIA and OncoLnc databases indicated that the upregulation of HSP90AA1 and HSP90AB1 was related to poor overall survival. In the cancer risk cohort, carcinoembryonic antigen (CEA), carbohydrate antigen 153 (CA153), HSP90AA1, T cells%, natural killer cells%, B cells%, neutrophil count, monocyte count, and d-dimer were incorporated into the nomogram. A high Harrell’s concordance index (C-index) value of 0.771 [95% confidence interval (CI), 0.725–0.817] could still be reached in the interval validation. In the metastasis risk cohort, predictors contained in the prediction nomogram included the use of CEA, CA153, HSP90AA1, carbohydrate antigen 125 (CA125), natural killer cells%, B cells%, platelet count, monocyte count, and d-dimer. The C-index was 0.844 (95% CI, 0.801–0.887) and it was well-calibrated. HSP90AA1 raised net clinical benefit of breast cancer onset and metastasis risk prediction nomogram in a range of risk thresholds (5–92%) and (1–90%).ConclusionOur study revealed that pretreatment plasma HSP90AA1 combined with other markers could conveniently predict the risk of breast cancer onset and metastasis.

Characterization of the tumor immune microenvironment (TIM) with multiplex immunohistochemistry (mIHC) in patients with breast cancer following treatment with MK-2206.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12109-e12109
Author(s):  
Douglas Kanter Marks ◽  
Robyn Denise Gartrell ◽  
Margueritta El Asmar ◽  
Thomas Hart ◽  
Yan Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Akt Inhibitor ◽  
Immune Microenvironment ◽  
Immune Biomarkers ◽  
Tumor Immune Microenvironment ◽  
Before And After ◽  
Infiltrating Lymphocytes ◽  
The Impact

e12109 Background: The PAM (PI3K/Akt/mTOR) signaling pathway has been implicated in the oncogenesis of multiple solid malignancies, including breast cancer (BC). Our aim is to characterize the TIM in a series of patients with operable stage I-III BC treated with MK-2206, an allosteric Akt inhibitor within a presurgical trial. In NCT01319539 , patients received 2 doses of MK-2206 with first dose at day -9 and second at day -2 from surgery. Methods: mIHC was performed using immune biomarkers (DAPI, CD3, CD8, CD4, FOXP3, CD68, Pancytokeratin) on full section (4uM) tissue slides from core biopsy specimens and postsurgical specimens of 10 patients - 5 treated with MK-2206, 5 paired controls. Images were taken using Vectra, a novel pathology workstation and analyzed using inForm software to perform cell classification and phenotyping. T- tests were used to compare biomarker changes before and after MK-2206. Results: Our preliminary analysis demonstrates that patients treated with MK-2206 exhibited an increase in median cytotoxic T-cells (CD3CD8+) density, as compared to the control population , which was statistically significant (87% vs.0.2%, p < 0.05). We did not identify a change in macrophage (CD68) or T helper/T reg (CD4/CD4FOXP3+) density following MK-2206 treatment in this small cohort. We are currently expanding our myeloid panel as well as performing additional tissue analysis to validate our findings. As data is exploratory no correction was made for multiple comparisons. Conclusions: Tumor infiltrating lymphocytes (TILs) are both prognostic of overall survival as well as predictive of response to neoadjuvant chemotherapy in BC. At present, there are currently both FDA approved therapies, as well as agents in clinical development that exert antineoplastic activity through the PAM pathway. Investigations that endeavour to understand the impact of these therapies on the tumor immune microenvironment may lead to both an increased understanding of the bioactivity of these agents and potentially identify aspects of the immune response which can be exploited in future therapeutics.

scholarly journals Statistical framework for studying the spatial architecture of the tumor immune microenvironment

2021 ◽  
Author(s):  
Christopher Wilson ◽  
Ram Thapa ◽  
Jordan Creed ◽  
Jonathan Nguyen ◽  
Carlos Moran Segura ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Immune Cells ◽  
Spatial Clustering ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Infiltrating Lymphocytes ◽  
Spatial Architecture

AbstractNew technologies, such as multiplex immunofluorescence microscopy (mIF), are being developed and used for the assessment and visualization of the tumor immune microenvironment (TIME). These assays produce not only an estimate of the abundance of immune cells in the TIME, but also their spatial locations; however, there are currently few approaches to analyze the spatial context of the TIME. Thus, we have developed a framework for the spatial analysis of the TIME using Ripley’s K, coupled with a permutation-based framework to estimate and measure the departure from complete spatial randomness (CSR) as a measure of the interactions between immune cells. This approach was then applied to ovarian cancer using mIF collected on intra-tumoral regions of interest (ROIs) and tissue microarrays (TMAs) from 158 high-grade serous ovarian carcinoma patients in the African American Cancer Epidemiology Study (AACES) (94 subjects on TMAs resulting in 259 tissue cores; 91 subjects with 254 ROIs). Cox proportional hazard models were constructed to determine the association of abundance and spatial clustering of tumor-infiltrating lymphocytes, cytotoxic T-cells, and regulatory T-cells, and overall survival. We found that EOC patients with high abundance and low spatial clustering of tumor-infiltrating lymphocytes and cytotoxic T-cells in their tumors had the best overall survival. In contrast, patients with low levels of regulatory T-cells but with a high level of spatial clustering (compare to those with a low level of spatial clustering) had better survival. These findings underscore the prognostic importance of evaluating not only immune cell abundance but also the spatial contexture of the immune cells in the TIME. In conclusion, the application of this spatial analysis framework to the study of the TIME could lead to the identification of immune content and spatial architecture that could aid in the determination of patients that are likely to respond to immunotherapies.

scholarly journals Inherited defects in natural killer cells shape tumor immune microenvironment, clinical outcome and immunotherapy response

2018 ◽  
Author(s):  
Xue Xu ◽  
Jianqiang Li ◽  
Jinfeng Zou ◽  
Xiaowen Feng ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Nk Cells ◽  
Natural Killer ◽  
Antigen Processing ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Cancer Types

AbstractTumor immune microenvironment (TIME) plays an important role in metastasis and immunotherapy. However, it has been not much known how to classify TIMEs and how TIMEs are genetically regulated. Here we showed that tumors were classified into TIME-rich, -intermediate and -poor subtypes which had significant differences in clinical outcomes, abundances of tumor-infiltrating lymphocytes (TILs), the degree of key immune programs’ activation, and immunotherapy response across 13 common cancer types (n= ∼6,000). Furthermore, TIME-intermediate/-poor patients had significantly more inherited genetic defects (i.e., functional germline variants) in natural killer (NK) cells, antigen processing and presentation (APP) and Wnt signaling pathways than TIME-rich patients, and so did cancer patients than non-cancer individuals (n=4,500). These results suggested that individuals who had more inherited defects in NK cells, APP and Wnt pathways had a higher risk of developing cancers. Moreover, in the 13 common cancers the number of inheritably defected genes of NK cells was significantly negative-correlated with patients’ survival, TILs’ abundance in TIMEs and immunotherapy response, suggesting that inherited defects in NK cells alone were sufficient to shape TILs’ recruitment, clinical outcome, and immunotherapy response, highlighting that NK cell activation was required in the 13 cancer types to drive the recruitment of immune troops into TIMEs. Thus, we proposed that cancer was a disease of NK cell inherited deficiencies. These results had implications in identifying of high-risk individuals based on germline genomes, implementing precision cancer prevention by adoptive transfer of healthy NK cells, and improving existing immunotherapies by combining of adoptive NK cell transfer (i.e., converting TIME-intermediate/-poor tumors into TIME-rich tumors) and anti-PD-1 or CAR-T therapy.ContactEW ([email protected])

scholarly journals Features of the Lymphoid Microenvironment in Invasive Ductal Breast Cancer

2021 ◽  
Vol 6 (6) ◽  
pp. 44-56
Author(s):  
L. I. Volos ◽  
◽  
A. P. Dudash
Keyword(s):  
Breast Cancer ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
Molecular Subtypes ◽  
Tumor Infiltrating Lymphocytes ◽  
Killer Cells ◽  
Invasive Margin ◽  
Invasive Ductal Breast Cancer ◽  
Ductal Breast Cancer ◽  
Degree Of Differentiation

The purpose of the study was to assess the distribution of tumor-infiltrating T-, B-lymphocytes and natural killer cells in various molecular subtypes of invasive ductal breast cancer and to establish their relationship with the degree of tumor differentiation. Materials and methods. The basis of the scientific work was a complex morphological, including immunohistochemical study of 193 cases of invasive ductal breast cancer. General histological processing of the samples was carried out in accordance with the standard technique. Immunohistochemical studies for CD3, CD20, CD56, ER, PR, c-erbB2, Ki-67 were performed according to the manufacturer's protocol with the control of samples. The grade of malignancy was determined according to the modified scheme of P. Scarff, H. Bloom and W. Richardson. The presence, localization, and expression intensity of diagnostic and prognostic biomarkers CD3, CD20, and CD56-positive cells (T-, B-, and natural killer cells, respectively) were determined using the new bioimage analysis software QuPath. Results and discussion. The differences obtained in our study varied depending on the subpopulations of immune cells and their location in the tumor tissue. The density of T and B lymphocytes was higher within the tumor and in the invasive margin in the non-luminal phenotypes compared to the luminal A and B phenotypes. Compared to the density of T-lymphocytes, the B-cell infiltrate was significantly (p <0.01) less pronounced in tumors of both luminal and non-luminal phenotypes. The lowest density of natural killer cells among tumor-infiltrating lymphocytes was found within the tumor of luminal subtypes. The percentage of infiltrates of T and B cells both within the tumor focus and in the invasive margin, as well as natural killer cells in the invasive margin, was significantly lower with G1 and G2 than with the degree of differentiation G3 (p <0.01). As for intratumoral natural killer cells, differences were found only between the degree of differentiation of G2 and G3, and the differences between G1 and G2 were not statistically significant (p> 0.05). Qualitative and quantitative assessment of the intensity of expression of T-, B- and natural killer cells also demonstrated a different degree of expression of lymphocytes, depending on the molecular subtype and location of the infiltrate. The luminal subtype A was characterized by a significant predominance of mild expression (2+) CD3 both within the tumor and in the invasive margin of the tumor (p <0.05), while in the luminal B and Her2 + phenotypes, the intensity of CD3 expression prevailed at the 1+ level. Triple negative tumors were characterized by strong expression of (3+) CD3 within the tumor and in the invasive margin of the tumor in all cases studied. Conclusion. Thus, tumor-infiltrating lymphocytes in different molecular subtypes of invasive ductal breast cancer can be considered a prognostic biomarker. Our results indicate a relationship between lymphoid infiltrate and the degree of differentiation in invasive ductal breast cancer, especially in less favorable molecular subtypes

scholarly journals The Ovarian Cancer Tumor Immune Microenvironment (TIME) as Target for Therapy: A Focus on Innate Immunity Cells as Therapeutic Effectors

2020 ◽  
Vol 21 (9) ◽  
pp. 3125 ◽  
Author(s):  
Denisa Baci ◽  
Annalisa Bosi ◽  
Matteo Gallazzi ◽  
Manuela Rizzi ◽  
Douglas M. Noonan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Microenvironment ◽  
New Era ◽  
Tumor Immune Microenvironment ◽  
Cancer Tumor ◽  
Immune Contexture ◽  
Infiltrating Lymphocytes

Ovarian cancer (OvCA) accounts for one of the leading causes of death from gynecologic malignancy. Despite progress in therapy improvements in OvCA, most patients develop a recurrence after first-line treatments, dependent on the tumor and non-tumor complexity/heterogeneity of the neoplasm and its surrounding tumor microenvironment (TME). The TME has gained greater attention in the design of specific therapies within the new era of immunotherapy. It is now clear that the immune contexture in OvCA, here referred as tumor immune microenvironment (TIME), acts as a crucial orchestrator of OvCA progression, thus representing a necessary target for combined therapies. Currently, several advancements of antitumor immune responses in OvCA are based on the characterization of tumor-infiltrating lymphocytes, which have been shown to correlate with a significantly improved clinical outcome. Here, we reviewed the literature on selected TIME components of OvCA, such as macrophages, neutrophils, γδ T lymphocytes, and natural killer (NK) cells; these cells can have a role in either supporting or limiting OvCA, depending on the TIME stimuli. We also reviewed and discussed the major (immune)-therapeutic approaches currently employed to target and/or potentiate macrophages, neutrophils, γδ T lymphocytes, and NK cells in the OvCA context.

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