The Contribution of Natural Killer and T-Cells to the Lymphokine-Activated Killer Cell Phenomenon

e15100 Background: Cancer treatment has entered the era of immune checkpoint inhibitors (ICI), but different tumors have different responses to ICI drugs. For example, non-small cell lung cancer and melanoma have higher response rates to ICIs than colorectal cancer and liver cancer patients. Previous studies have shown that tumor immune microenvironment have a great impact on the efficacy of ICI. Methods: This study retrospectively included pan-cancer patient specimens, using multiple fluorescent labeling immunohistochemistry to explore the differences in the immune microenvironment of different tumors. Shapiro-Wilk was used for normality test, and ANOVA or Kruskal Wallis test was used according to the results. Two-sided P < 0.05 was considered a significant difference. Results: The study included 308 patients, including 119 (38.6%) NSCLC patients, 72 (23.4%) Colorectal cancer patients, 51 (16.6%) Hepatobiliary cancer patients and 66 (21.4%) Others types of cancer patients. Among them, there was 192 (62.3%) Male, and 116 (37.7%) Female, and the median age was 57 (50-66). The proportion of CD8+ T cells and natural killer cell in tumor was statistically different. The proportion of CD8+ T cells in NSCLC, Colorectal cancer, Hepatobiliary cancer and others was 2.16%, 1%, 1.77% and 2.63%, p < 0.01; the proportion of natural killer cell was 16.44 %, 4.91%, 5.58% and 3.29%, p < 0.01. Conclusions: Different tumor types have different immune microenvironments. These results may provide valuable clues for future ICI trail design.

Download Full-text

Abstract 26: IL-17 Causes Hypertension, Reduced Fetal Weight And Natural Killer Cell Activation In The Absence Of T Cells

Hypertension ◽

10.1161/hyp.78.suppl_1.26 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Sarah J Fitzgerald ◽

James Hogg ◽

Evangeline Deer ◽

Nathan Campbell ◽

Owen Herrock ◽

...

Keyword(s):

T Cells ◽

Natural Killer ◽

Rat Model ◽

Cell Activation ◽

Nk Cell ◽

Killer Cell ◽

Interleukin 17 ◽

Sprague Dawley ◽

Th Cells ◽

Atp Production

Preeclampsia (PE) is characterized by new onset hypertension (HTN), intrauterine growth restriction (IUGR), multi-organ dysfunction, and is associated with increased inflammatory cytokines, such as interleukin 17 (IL-17). More recent studies demonstrate a role for mitochondrial (mt) dysfunction/mtROS in the pathogenesis of PE. Although we have shown T helper cells from a rat model of PE cause HTN and mt dysfunction the causative factors for mt dysfunction are still being identified. In addition, we have shown that IL-17 cause HTN, IUGR and activate natural killer (NK) cells, and cause mt dysfunction in pregnant Sprague Dawley rats. However, in our previous studies we couldn’t differentiate the effect of activated TH cells versus IL-17 to cause these characteristics of PE. The athymic nude rat model lacks mature T cells but does have other components of the immune system, and will thus allow us to examine the role of IL-17 in the absence of TH cells in the pathophysiology of PE. We hypothesize that in the absence of T cells IL-17 induces HTN, NK cell activation and IUGR which is associated with renal and placental mt dysfunction during pregnancy. To test our hypothesis, IL-17 (150 pg/day) was infused via osmotic minipumps inserted on gestation day (GD) 14. Blood pressure (MAP) and mt function were measured on GD19 and were compared to untreated pregnant (NP) athymic nude rats. In response to IL-17; MAP increased from 95±4mmHg in NP(n=6) to 115±2 in NP+IL-17(n=6) (p<0.001); pup weight decreased from 1.46±0.2 g in NP (n=6) to 0.98±0.07g in NP+IL-17 (n=6) (p<0.05); NK cell activation increased from 0±0 %lymphocytes in NP (n=3) to 0.4±0.1% lymphocytes in NP+IL-17 rats (n=6). Interestingly, placental mtROS reduced 54% fold compared to NP and renal mtROS reduced 51.2% compared to NP. ATP production increased from 15.53±1.6 pmol of O2/sec/mg in NP (n=3) to 105.5±91 pmol of O2/sec/mg in NP+IL-17 (n=3) in the placenta, and from 1196±460 pmol of O2/sec/mg in NP (n=4) to 2016±951 pmol of O2/sec/mg NP+IL17 (n=4) in the kidney. These results show that although IL-17 induces HTN, IUGR, and NK cell activation independent of T cells, T cells are necessary for reduced mitochondrial function observed in PE and in rat models of placental ischemia.

Download Full-text

Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

Journal of Translational Medicine ◽

10.1186/s12967-021-03203-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Hee Young Na ◽

Yujun Park ◽

Soo Kyung Nam ◽

Jiwon Koh ◽

Yoonjin Kwak ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

B Cells ◽

Nk Cells ◽

Natural Killer ◽

Immune Cells ◽

Nk Cell ◽

Critical Role ◽

Killer Cell ◽

Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

Download Full-text

Alteration of inhibitory and activating natural killer cell receptor expression on T cells in human immunodeficiency virus-infected Chinese

Microbiology and Immunology ◽

10.1111/j.1348-0421.2011.00372.x ◽

2011 ◽

Vol 55 (10) ◽

pp. 715-725 ◽

Cited By ~ 1

Author(s):

Yongjun Jiang ◽

Shanshan Wu ◽

Fangyuan Zhou ◽

Tristan Bice ◽

Zining Zhang ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Natural Killer Cell ◽

Natural Killer ◽

Killer Cell ◽

Cell Receptor ◽

Receptor Expression ◽

Natural Killer Cell Receptor ◽

Immunodeficiency Virus

Download Full-text

Defining a novel subset of CD1d‐dependent type II natural killer T cells using natural killer cell‐associated markers

Scandinavian Journal of Immunology ◽

10.1111/sji.12794 ◽

2019 ◽

Vol 90 (3) ◽

Cited By ~ 2

Author(s):

Avadhesh Kumar Singh ◽

Sara Rhost ◽

Linda Löfbom ◽

Susanna L. Cardell

Keyword(s):

T Cells ◽

Natural Killer Cell ◽

Natural Killer ◽

Killer Cell ◽

Natural Killer T Cells ◽

Type Ii ◽

Killer T Cells ◽

Dependent Type ◽

Natural Killer T

Download Full-text

Enhanced adaptive immune responses in lung adenocarcinoma through natural killer cell stimulation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1904253116 ◽

2019 ◽

Vol 116 (35) ◽

pp. 17460-17469 ◽

Cited By ~ 12

Author(s):

Leah Schmidt ◽

Banu Eskiocak ◽

Ryan Kohn ◽

Celeste Dang ◽

Nikhil S. Joshi ◽

...

Keyword(s):

T Cells ◽

Lung Adenocarcinoma ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Production Capacity ◽

Dependent Manner ◽

Cell Stimulation ◽

Established Disease

Natural killer (NK) cells inhibit tumor development in mouse models and their presence in tumors correlates with patient survival. However, tumor-associated NK cells become dysfunctional; thus, stimulation of NK cells in cancer is emerging as an attractive immunotherapeutic strategy. In a mouse model of lung adenocarcinoma, NK cells localized to tumor stroma with immature phenotypes and low functional capacity. To test their responsiveness within established disease, we engineered a system for inducible expression of activating ligands in tumors. After stimulation, NK cells localized inside tumors, with increased cytokine production capacity. Strikingly, T cells were also recruited to tumors in an NK cell-dependent manner, and exhibited higher functionality. In neoantigen-expressing tumors, NK cell stimulation enhanced the number and function of tumor-specific T cells and, in long-term settings, reduced tumor growth. Thus, even in established disease NK cells can be activated to contribute to antitumor immunity, supporting their potential as an important target in cancer immunotherapy.

Download Full-text

Inhibition of T Cell and Promotion of Natural Killer Cell Development by the Dominant Negative Helix Loop Helix Factor Id3

Journal of Experimental Medicine ◽

10.1084/jem.186.9.1597 ◽

1997 ◽

Vol 186 (9) ◽

pp. 1597-1602 ◽

Cited By ~ 202

Author(s):

Mirjam H.M. Heemskerk ◽

Bianca Blom ◽

Garry Nolan ◽

Alexander P.A. Stegmann ◽

Arjen Q. Bakker ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Natural Killer ◽

Progenitor Cells ◽

Killer Cell ◽

Cell Development ◽

Dominant Negative ◽

Bhlh Transcription Factor ◽

Lineage Specification ◽

Helix Loop Helix

Bipotential T/natural killer (NK) progenitor cells are present in the human thymus. Despite their bipotential capacity, these progenitors develop predominantly to T cells in the thymus. The mechanisms controlling this developmental choice are unknown. Here we present evidence that a member(s) of the family of basic helix loop helix (bHLH) transcription factors determines lineage specification of NK/T cell progenitors. The natural dominant negative HLH factor Id3, which blocks transcriptional activity of a number of known bHLH factors, was expressed in CD34+ progenitor cells by retrovirus-mediated gene transfer. Constitutive expression of Id3 completely blocks development of CD34+ cells into T cells in a fetal thymic organ culture (FTOC). In contrast, development into NK cells in an FTOC is enhanced. Thus, the activity of a bHLH transcription factor is necessary for T lineage differentiation of bipotential precursors, in the absence of which a default pathway leading to NK cell development is chosen. Our results identify a molecular switch for lineage specification in early lymphoid precursors of humans.

Download Full-text