• T cell
• galectin-9
• immune
• inhibitors
• strategies

• PBMC
• WGCNA
• cancer diagnosis
• logistic regression
• scRNA-seq

• Humans
• Leukocytes, Mononuclear
• Single-Cell Gene Expression Analysis
• Neoplasms/diagnosis
• Neoplasms/genetics
• Cell Differentiation
• Cell Transformation, Neoplastic

• Gastric cancer
• Immune cells
• Immunotherapy
• Programmed cell death receptor-1
• Tumor microenvironment

• Humans
• Stomach Neoplasms/therapy
• Immune Checkpoint Inhibitors
• Immunotherapy
• T-Lymphocytes
• Tumor Microenvironment

• immune function
• nk cell
• phellinus linteus
• randomized controlled trial

• Basidiomycota
• Humans
• Lactate Dehydrogenases
• Phellinus
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use

Gastric cancer is still one of the leading causes of death caused by cancer in developing countries. The emerging role of immunotherapy in cancer treatment has led to more research to elucidate the roles of essential immune cells in gastric cancer prognosis. We reviewed the roles of immune cells including T cells, B cells, dendritic cells, macrophages and natural killer cells in gastric cancer. Although the studies conducted on the roles of immune cells in gastric cancer pathogenesis produced conflicting results, understanding the roles of immune cells in gastric cancer will help us to harness them for application in immunotherapy for better prognosis and management of gastric cancer patients.

Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world’s leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late stage of cancer progression. Thus, the prognosis of gastric cancer is poor, and the current treatment for improving patients’ outcomes involves the application of surgery and chemotherapy. Immunotherapy is one of the most recent therapies for gastric cancer, whereby the immune system of the host is programmed to combat cancer cells, and the therapy differs based upon the patient’s immune system. However, an understanding of the role of immune cells, namely the cell-mediated immune response and the humoral immune response, is pertinent for applications of immunotherapy. The roles of immune cells in the prognosis of gastric cancer have yielded conflicting results. This review discusses the roles of immune cells in gastric cancer pathogenesis, specifically, T cells, B cells, macrophages, natural killer cells, and dendritic cells, as well as the evidence presented thus far. Understanding how cancer cells interact with immune cells is of paramount importance in designing treatment options for gastric cancer immunotherapy.

• B cells
• T cells
• dendritic cells
• gastric cancer
• immune cells
• immune response
• macrophages
• natural killer cells

Metformin, a drug prescribed to treat type 2 diabetes, has been reported to possess antitumor activity via immunity activation. However, the influence of metformin on natural killer (NK) cells is not fully understood. Here, we investigated whether metformin exerts a potent anticancer effect by activating NK cells. The results showed that sustained exposure to metformin enhances the cytolytic activity of NK-92 cells. Moreover, this enhancement of cytotoxicity by metformin was also observed in NK cells from healthy peripheral blood and cancer patient ascites. Mechanistically, metformin induced activation of the JAK1/2/3/STAT5 and AKT/mTOR pathways in a p38 MAPK-dependent manner rather than an AMPK-dependent manner. In vivo experiments, metformin also improved cancer surveillance of NK cells in mouse models of lymphoma clearance and metastatic melanoma. Additionally, combination treatment with metformin and anti-PD-1 antibodies increased the therapy response rates of B16F10 melanoma. Moreover, metformin treatment increased NK cell and T cell infiltration in tumors. Therefore, these results provide a deeper understanding of metformin on the effector function of NK cells and will contribute to the development and applications of metformin in cancer treatment strategies.

• Metformin
• NK cells
• cancer surveillance
• immunotherapy
• p38 MAPK

Strategies to enhance the preferential accumulation and activation of Natural Killer (NK) cells in the tumor microenvironment can be expected to increase the efficacy of NK cell-based cancer immunotherapy. In this study, we report that a bispecific single domain antibody (VHH) that targets CD16 (FcRγIII) on NK cells and the epidermal growth factor receptor (EGFR) on tumor cells can be used to target and enhance cytolysis of cancer cells. The bispecific VHH enhanced NK cell activation and cytotoxicity in an EGFR- and CD16-dependent and KRAS-independent manner. Moreover, the bispecific VHH induced stronger activity of cancer patient-derived NK cells and resulted in tumor control in a co-culture of metastatic colorectal cancer cells and either autologous peripheral blood mononuclear cells or allogeneic CD16⁺ NK cells. We believe that this novel approach could represent a valid therapeutic strategy either alone or in combination with other NK cell-based therapies.

The ability to kill tumor cells while maintaining an acceptable safety profile makes Natural Killer (NK) cells promising assets for cancer therapy. Strategies to enhance the preferential accumulation and activation of NK cells in the tumor microenvironment can be expected to increase the efficacy of NK cell-based therapies. In this study, we show binding of a novel bispecific single domain antibody (VHH) to both CD16 (FcRγIII) on NK cells and the epidermal growth factor receptor (EGFR) on tumor cells of epithelial origin. The bispecific VHH triggered CD16- and EGFR-dependent activation of NK cells and subsequent lysis of tumor cells, regardless of the KRAS mutational status of the tumor. Enhancement of NK cell activation by the bispecific VHH was also observed when NK cells of colorectal cancer (CRC) patients were co-cultured with EGFR expressing tumor cells. Finally, higher levels of cytotoxicity were found against patient-derived metastatic CRC cells in the presence of the bispecific VHH and autologous peripheral blood mononuclear cells or allogeneic CD16 expressing NK cells. The anticancer activity of CD16-EGFR bispecific VHHs reported here merits further exploration to assess its potential therapeutic activity either alone or in combination with adoptive NK cell-based therapeutic approaches.

• CD16
• EGFR
• NK cells
• bispecific VHH
• single domain antibodies

• R01 CA203348 NCI NIH HHS
• R01CA203348 NIH HHS

• NK cell activity
• XLP-1
• bispecific antibodies
• multiple myeloma
• receptor synergy

• Antibodies, Bispecific/immunology
• HEK293 Cells
• Humans
• Interferon-gamma/metabolism
• Killer Cells, Natural/immunology
• Killer Cells, Natural/metabolism
• Lymphocyte Activation/immunology
• Lymphoproliferative Disorders/diagnosis
• Lymphoproliferative Disorders/immunology
• Multiple Myeloma/diagnosis
• Multiple Myeloma/immunology
• NK Cell Lectin-Like Receptor Subfamily K/immunology
• Proof of Concept Study
• Signaling Lymphocytic Activation Molecule Family/immunology
• Single-Chain Antibodies/immunology

• Advanced gastric cancer
• Natural killer cell activity
• Trastuzumab

• bile duct neoplasms
• immunologic surveillance
• natural killer cell
• pancreatic neoplasms

Radiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT.

EDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20–30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry.

Patients with non-recurrent SCCHN had significantly lower proportions of CD19⁺ B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3⁺ T and CD3⁺/CD4⁺ T helper cells continuously decreased between t0 and t3, whereas that of CD8⁺ cytotoxic T cells and CD3⁺/CD56⁺ NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4⁺/CD25⁺/FoxP3⁺ regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4⁺ T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56⁺/CD69⁺, CD3⁻/CD56⁺, CD3⁻/CD94⁺, CD3⁻/NKG2D⁺, CD3⁻/NKp30⁺, CD3⁻/NKp46⁺) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5).

Monitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed.

Observational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668.

The online version contains supplementary material available at 10.1186/s13014-021-01868-5.

• Immunophenotyping
• Lymphocyte subpopulations
• NK cell subsets
• Prediction of locoregional recurrence
• Radiochemotherapy
• SCCHN

• NK cell activity
• cancer
• chemotherapy
• natural killer cells
• physical exercise

• Breast Neoplasms/drug therapy
• Breast Neoplasms/immunology
• Breast Neoplasms/surgery
• Breast Neoplasms/therapy
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/immunology
• Colonic Neoplasms/surgery
• Colonic Neoplasms/therapy
• Exercise/immunology
• Female
• Humans
• Interleukin-6/blood
• Killer Cells, Natural/drug effects
• Killer Cells, Natural/physiology
• Male
• Middle Aged
• Neoadjuvant Therapy/adverse effects
• Pilot Projects

• General anesthesia
• Gynecologic cancer
• Prognosis
• Propofol
• Recurrence
• Sevoflurane
• Survival

Natural Killer (NK) cells are innate lymphocytes that play an important role in the immune response against cancer. Their activity is controlled by a balance of inhibitory and activating receptors, which in cancer can be skewed to favor their suppression in support of immune escape. It is therefore imperative to find ways to optimize their antitumor functionality. In this review, we explore and discuss how their activity influences, or even mediates, the efficacy of various anti-cancer therapies and, vice versa, how their activity can be affected by these therapies. Knowledge of the mechanisms underlying these observations could provide rationales for combining anti-cancer treatments with strategies enhancing NK cell function in order to improve their therapeutic efficacy.

Natural Killer (NK) cells are innate immune cells with the unique ability to recognize and kill virus-infected and cancer cells without prior immune sensitization. Due to their expression of the Fc receptor CD16, effector NK cells can kill tumor cells through antibody-dependent cytotoxicity, making them relevant players in antibody-based cancer therapies. The role of NK cells in other approved and experimental anti-cancer therapies is more elusive. Here, we review the possible role of NK cells in the efficacy of various anti-tumor therapies, including radiotherapy, chemotherapy, and immunotherapy, as well as the impact of these therapies on NK cell function.

• NK cells
• anti-cancer therapies
• cancer
• checkpoint inhibitors
• chemotherapy
• local ablation therapies
• oncolytic virus
• protein kinase inhibitors
• radiotherapy

In the process of epithelial-mesenchymal transition (EMT), epithelial cancer cells transdifferentiate into mesenchymal-like cells with high motility and aggressiveness, resulting in the spread of tumor cells. Immune cells and inflammation in the tumor microenvironment are the driving factors of EMT, but few studies have explored the core targets of the interaction between EMT and tumor immune cells. We analyzed thousands of cases of gastric cancer and gastric tissue specimens of TCGA, CPTAC, GTEx and analyzing QPCR and IHC data of 56 gastric cancer patients in SYSU Gastric Cancer Research Center. It was known that EMT has an important connection with the infiltration of NK cells, and that the expression of vinculin may be the target of the phenomenon. The increased expression of vinculin is closely related to the aggressiveness and distant metastasis of cancer, which affects the survival prognosis of the patient. Moreover, through in vitro experiments under 3D conditions, we found that vinculin, cell invasion and metastasis are clearly linked. VCL can affect EMT and tumor immunity by regulating EPCAM gene expression. The role and mechanism of action of vinculin have been controversial, but this molecule may downregulate EpCAM (epithelial cellular adhesion molecule) and its own role in gastric cancer through DNA methylation, causing NK cells to enrich into tumor cells and kill tumor cells. At the same time, it promotes the occurrence of EMT, which in turn causes tumor metastasis and thus poorer prognosis.

• DNA methylation
• NK cell Infiltration
• epithelial-mesenchymal transition
• gastric cancer
• vinculin

Natural killer (NK) cells are cytotoxic innate lymphocytes endowed with a unique ability to kill a broad spectrum of cancer and virus-infected cells. Given their key contribution to diverse diseases, the measurement of NK cell activity (NKA) has been used to estimate disease prognosis or the effect of therapeutic treatment. Currently, NKA assays are primarily based on cumbersome procedures related to careful labeling and handling of target cells and/or NK cells, and they require a rapid isolation of peripheral blood mononuclear cells (PBMCs) which often necessitates a large amount of blood. Here, we developed an ELISA-based whole blood (WB) NKA assay involving engineered target cells (P815-ULBP1+CD48) providing defined and synergistic stimulation for NK cells via NKG2D and 2B4. WB collected from healthy donors (HDs) and patients with multiple myeloma (MM) was stimulated with P815-ULBP1+CD48 cells combined with IL-2. Thereafter, it utilized the serum concentrations of granzyme B and IFN-γ originating in NK cells as independent and complementary indicators of NKA. This WB NKA assay demonstrated that MM patients exhibit a significantly lower NKA than HDs following stimulation with P815-ULBP1+CD48 cells and had a good correlation with the commonly used flow cytometry-based PBMC NKA assay. Moreover, the use of P815-ULBP1+CD48 cells in relation to assessing the levels of NKG2D and 2B4 receptors on NK cells facilitated the mechanistic study and led to the identification of TGF-β1 as a potential mediator of compromised NKA in MM. Thus, our proposed WB NKA assay facilitates the reliable measurement of NKA and holds promise for further development as both a clinical and research tool.

• 2B4
• NKG2D
• TGF-β1
• activity assay
• multiple myeloma
• natural killer cells

• Case-Control Studies
• Flow Cytometry
• Humans
• Killer Cells, Natural/immunology
• Killer Cells, Natural/metabolism
• Leukocytes, Mononuclear/immunology
• Leukocytes, Mononuclear/metabolism
• Multiple Myeloma/immunology
• Multiple Myeloma/metabolism
• Receptors, Natural Killer Cell/metabolism

A growing number of studies suggest that cancer-associated fibroblasts (CAFs) modulate both myeloid and lymphoid cells through secretion of molecules (i.e., chemical function) and production of the extracellular matrix (ECM), i.e., physical function. Even though targeting functions CAFs is a relevant strategy, published clinical trials solely aimed at targeting the stroma showed disappointing results, despite being based on solid preclinical evidence. Our review dissects the interactions between CAFs and immune cells and explains how a deeper understanding of CAF subpopulations is the cornerstone to propose relevant therapies that will ultimately improve survival of patients with cancer.

Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential applications in the field of cancer immunotherapy. Indeed, CAFs are highly involved in tumor immune evasion by physically impeding the immune system and interacting with both myeloid and lymphoid cells. However, CAFs do not represent a single cell entity but are divided into several subtypes with different functions that may be antagonistic. Considering that CAFs are orchestrators of the tumor microenvironment and modulate immune cells, targeting their functions may be a promising strategy. In this review, we provide an overview of (i) the mechanisms involved in immune regulation by CAFs and (ii) the therapeutic applications of CAFs modulation to improve the antitumor immune response and the efficacy of immunotherapy.

• cancer-associated fibroblasts
• cell communication
• immunology
• tumor microenvironment

High-dose recombinant interleukin 2 (IL2) therapy has been shown to be successful in renal cell carcinoma and metastatic melanoma. However, systemic administration of high doses of IL2 can be toxic, causing capillary leakage syndrome and stimulating pro-tumor immune response. One of the strategies to reduce the systemic toxicity of IL2 is the use of mesenchymal stem cells (MSCs) as a vehicle for the targeted delivery of IL2. Human adipose tissue-derived MSCs were transduced with lentivirus encoding IL2 (hADSCs-IL2) or blue fluorescent protein (BFP) (hADSCs-BFP). The proliferation, immunophenotype, cytokine profile and ultrastructure of hADSCs-IL2 and hADSCs-BFP were determined. The effect of hADSCs on activation of peripheral blood mononuclear cells (PBMCs) and proliferation and viability of SH-SY5Y neuroblastoma cells after co-culture with native hADSCs, hADSCs-BFP or hADSCs-IL2 on plastic and Matrigel was evaluated. Ultrastructure and cytokine production by hADSCs-IL2 showed modest changes in comparison with hADSCs and hADSCs-BFP. Conditioned medium from hADSC-IL2 affected tumor cell proliferation, increasing the proliferation of SH-SY5Y cells and also increasing the number of late-activated T-cells, natural killer (NK) cells, NKT-cells and activated T-killers. Conversely, hADSC-IL2 co-culture led to a decrease in SH-SY5Y proliferation on plastic and Matrigel. These data show that hADSCs-IL2 can reduce SH-SY5Y proliferation and activate PBMCs in vitro. However, IL2-mediated therapeutic effects of hADSCs could be offset by the increased expression of pro-oncogenes, as well as the natural ability of hADSCs to promote the progression of some tumors.

• cancer therapy
• immunotherapy
• interleukin 2
• mesenchymal stem cells
• neuroblastoma

• TGF-β1
• cytotoxicity
• natural killer cells
• pancreatic cancer
• prognosis

• Biomarkers, Tumor/immunology
• Cell Degranulation/immunology
• Cytotoxicity, Immunologic/immunology
• Disease Progression
• Humans
• Killer Cells, Natural/immunology
• Killer Cells, Natural/pathology
• Pancreatic Neoplasms/immunology
• Pancreatic Neoplasms/pathology
• Transforming Growth Factor beta1/immunology

Recent years have seen a renaissance in the research linking inflammation and cancer with immune cells playing a central role in smouldering inflammation in the tumor microenvironment. Diverse immune cell types infiltrate the tumor microenvironment, and the dynamic tumor-immune cell interplay gives rise to a rich milieu of cytokines and growth factors. Fundamentally, this intricate cross-talk creates the conducive condition for tumor cell proliferation, survival and metastasis. Interestingly, the prominent impact of immune cells is expounded in their contrary pro-tumoral role, as well as their potential anti-cancer cellular weaponry. The latter is known as immunotherapy, a concept born out of evidence that tumors are susceptible to immune defence and that by manipulating the immune system, tumor growth can be successfully restrained. Naturally, a deeper understanding of the multifaceted roles of various immune cell types thus contributes toward developing innovative anti-cancer strategies. Therefore, in this review we first outline the roles played by the major immune cell types, such as macrophages, neutrophils, natural killer cells, T cells and B cells. We then explain the recently-explored strategies of immunomodulation and discuss some important approaches via an immunology perspective.

• Cancer
• Immune checkpoint
• Immunotherapy
• Inflammation
• Nanoparticles

Although decreased natural killer cell activity (NKA) has been observed in many solid cancers, clinical implication of NKA has been scarcely investigated in lung cancer. The objective of this study was to evaluate the potential of using NKA to support diagnosis of non-small cell lung cancer (NSCLC).

We prospectively evaluated and compared peripheral blood NKA using a novel interferon-gamma releasing assay in healthy population (n=40), patients with benign lung disease (n=40), and those with NSCLC (n=71). We explored the correlation between NKA and clinical parameters and assessed diagnostic performance of NKA for NSCLC using receiver operating characteristic curve analysis.

Median NKA values in healthy population, patients with benign lung disease, and those with NSCLC were 1,364.2, 1,438.2, and 406.3 pg/mL, respectively. NKA in NSCLC patients was significantly lower than that in the other two control groups (both P<0.001). At a cutoff value of NKA at 391.0 pg/mL, the area under the curve was 0.762 (95% CI: 0.685–0.838, P<0.001), with a sensitivity of 52.3%, a specificity of 91.0%, a positive predictive value of 85.3%, and a negative predictive value of 65.4% for the diagnosis of NSCLC. Multivariate analysis demonstrated that diagnosis of NSCLC is the only clinical parameter that was significantly associated with NKA (P<0.001).

This pilot study showed that patients with low NKA were more likely to have lung cancer. Further studies are warranted in order to establish the clinical utility of NKA test for diagnosing lung cancer.

• ELISA
• diagnosis
• interferon-gamma
• lung cancer
• natural killer cell

Gastric cancer (GC) is one of the most common cancers, with a high incidence of cancer death. Despite various therapeutic approaches, the cures and prognosis of advanced GC remain poor. Natural killer (NK) cells, which are known as important lymphocytes in innate immunity, play vital roles in suppressing GC initiation, progression, and metastases. A wide range of clinical settings shows that increasing the number of NK cells or improving NK cell antitumor activity is promising in GC patients. NK cell adoptive therapy (especially expanded NK cells) is a safe and well-tolerated method, which can enhance NK cell cytotoxicity against GC. Meanwhile, cytokines, immunomodulatory drugs, immune checkpoint blockades, antibodies, vaccines, and gene therapy have been found to directly or indirectly activate NK cells to improve their killing activity toward GC. In this review, we summarize recent advancements in the relationship between NK cells and GC and point out all the innovative strategies that can enhance NK cells' function to inhibit the growth of GC.

• adoptive therapy
• checkpoint blockades
• gastric cancer
• immunity
• natural killer cells

• IGF-1
• cancer surveillance
• cytotoxicity
• ginsenoside
• natural killer cell

• California sea lion
• Cryopreserved lymph nodes
• Cytotoxicity
• Lymphocyte proliferation
• NK cells
• PCBs

• Animals
• Cell Proliferation
• Dioxins
• Polychlorinated Biphenyls/chemistry
• Polychlorinated Dibenzodioxins/chemistry
• Sea Lions

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Immunological/pharmacology
• B7-H1 Antigen/immunology
• B7-H1 Antigen/metabolism
• Cetuximab/pharmacology
• Female
• Head and Neck Neoplasms/immunology
• Head and Neck Neoplasms/mortality
• Head and Neck Neoplasms/pathology
• Head and Neck Neoplasms/therapy
• Humans
• Interferon-gamma/metabolism
• Killer Cells, Natural/drug effects
• Killer Cells, Natural/immunology
• Killer Cells, Natural/pathology
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/pathology
• Male
• Middle Aged
• Natural Cytotoxicity Triggering Receptor 1/metabolism
• Programmed Cell Death 1 Receptor/immunology
• Programmed Cell Death 1 Receptor/metabolism
• Survival Rate
• Treatment Outcome

• R01 DE019727 NIDCR NIH HHS
• P30 CA047904 NCI NIH HHS
• R01 CA110249 NCI NIH HHS
• P50 CA097190 NCI NIH HHS
• T32 CA060397 NCI NIH HHS

• NK cell
• NK cell activity
• immunoregulation
• interferon gamma
• neutrophil-to-lymphocyte ratio

• therapy response
• treatment resistance
• tumor microenvironment

• Antineoplastic Agents/pharmacology
• Drug Resistance
• Humans
• Neoplasm Staging
• Neoplasms/drug therapy
• Neoplasms/pathology
• Treatment Outcome
• Tumor Microenvironment/drug effects
• Tumor Microenvironment/physiology

• Arabinoxylan
• BioBran
• MGN-3
• Ribraxx
• adenocarcinoma
• adjunct therapy
• cancer
• carcinogenesis
• chemoprotective
• chemotherapy
• complementary medicine
• immunomodulation
• immunotherapy
• rice bran
• systematic review

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Clinical Trials as Topic
• Complementary Therapies/methods
• Humans
• Immunologic Factors/pharmacology
• Immunologic Factors/therapeutic use
• Neoplasms/drug therapy
• Randomized Controlled Trials as Topic
• Xylans/pharmacology
• Xylans/therapeutic use

• dendritic cells
• immune cells
• mast cells
• non-small cell lung cancer
• tumor associated macrophages

• immune cells
• peripheral blood
• prediction
• prognosis
• tools
• tumor
• tumor-infiltrating

• diagnostic marker
• gastric cancer
• interferon-gamma
• natural killer cell activity

Background and Objective: Natural killer (NK) cells are known to have an effect on the prevention of tumorigenesis for the initial cancer, as well as the metastatic cancer. For the past several years, the relationship between cancer and inflammation has been actively studied in preclinical and clinical settings, but there are no reports on alterations in and correlation for NK cell activity (NKA) and systemic inflammatory markers. Accordingly, this study aimed to measure correlation between NKA and the levels of other systemic inflammatory markers in patients with gastric, breast, and pancreatic cancer who received Wheel Balance Cancer Therapy (WBCT). Methods: Forty-two electronic charts of patients with gastric, breast, and pancreatic cancer treated with WBCT from February 1, 2015 to September 30, 2015, were reviewed retrospectively. These charts were statistically analyzed, looking for alterations of and correlation for NKA and the expressions of systemic inflammatory markers. Results: Patients with a NKA of under 300 pg/mL at admission showed significantly higher erythrocyte sedimentation rate (ESR) and neutrophil-to-lymphocyte ratio (NLR) values and decreasing NLR values due to WBCT than patients with an NKA greater than 300 pg/mL. As a result of the correlation analysis between NKA and the levels of the systemic inflammatory markers, NKA showed significant negative correlation with NLR, ESR, and fibrinogen values. Conclusions: Negative correlation was identified between NKA and NLR, NKA and ESR, and NKA and fibrinogen in patients with heterogeneous cancer patients.

• erythrocyte sedimentation rate
• fibrinogen
• natural killer cell activity
• neutrophil-to-lymphocyte ratio
• systemic inflammatory marker

Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor–ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer.

• Anti-CTLA-4
• IL-15
• NK cells
• PD-1
• TIM-3
• melanoma

• DNA demethylating agents
• cancer-associated fibroblast
• cytotoxic T lymphocyte
• dendritic cell
• histone deacetylase inhibitors
• macrophage
• mesenchymal stem cell
• microRNA
• myeloid-derived suppressor cell
• natural killer cell
• regulatory T cell
• tumour-associated antigens

• Humans
• Immune System/drug effects
• Immune System/physiopathology
• Immune System/radiation effects
• Immunotherapy
• Neoplasms/immunology
• Neoplasms/psychology
• Neoplasms/therapy

• CD107a
• IFN-γ
• Natural killer cells
• Reference intervals

NK cells contribute to tumour surveillance, inhibition of growth and dissemination by cytotoxicity, secretion of cytokines and interaction with immune cells. Their precise role in human breast cancer is unclear and the effect of therapy poorly studied. The purpose of our study was to characterise NK cells in women with large (≥3 cm) and locally advanced (T3–4, N1–2, M0) breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC) and surgery, and to ascertain their possible contribution to a pathological complete response (pCR).

Women with LLABCs (n = 25) and healthy female donors [HFDs (n = 10)] were studied. Pathological responses in the breast were assessed using established criteria. Blood samples were collected pre and post NAC and surgery. Flow cytometry and labelled monoclonal antibodies established absolute numbers (AbNs) and percentages (%) of NK cells, and expressing granzyme B/perforin and NKG2D. In vitro NK cytotoxicity was assessed and NK cells and cytokines (IL-2, INF-γ, TGF-β) documented in tumours using immunohistochemical techniques. Data was analysed by SPSS.

Women with LLABCs had significantly reduced AbNs (160.00 ± 40.00 cells/µl) but not % of NK cells, compared with HFDs (NK: 266.78 ± 55.00 cells/µl; p = 0.020). NAC enhanced the AbN (p = 0.001) and % (p = 0.006) of NK cells in patients with good pathological responses. Granzyme B⁺/perforin⁺ cells were significantly reduced (43.41 ± 4.00%), compared with HFDs (60.26 ± 7.00%; p = 0.003). NAC increased the % in good (p = 0.006) and poor (p = 0.005) pathological responders. Pretreatment NK cytotoxicity was significantly reduced in good (37.80 ± 8.05%) and poor (22.80 ± 7.97%) responders (p = 0.001) but remained unchanged following NAC. NK-NKG2D⁺ cells were unaltered and unaffected by NAC; NKG2D expression was increased in patients with a pCR (p = 0.001). Surgery following NAC was not beneficial, except in those with a pCR. Tumour-infiltrating NK cells were infrequent but increased peritumourally (p = 0.005) showing a significant correlation (p = 0.004) between CD56⁺ cells and grade of response. Tumour cytokines had no effect.

Women with LLABCs have inhibited blood innate immunity, variably reversed by NAC (especially with tumour pCRs), which returned to pretreatment levels following surgery. These and in situ tumour findings suggest a role for NK cells in NAC-induced breast pCR.

• Activation
• GSK-3
• Natural killer cell
• Receptor
• Signaling

• ELISA
• High-throughput screening
• IFN-γ
• NK cell activity
• Simple assay

• Adult
• Aged
• Aged, 80 and over
• Colorectal Neoplasms/blood
• Colorectal Neoplasms/immunology
• Enzyme-Linked Immunosorbent Assay/methods
• Female
• High-Throughput Screening Assays/methods
• Humans
• Interferon-gamma/blood
• Interferon-gamma/immunology
• Killer Cells, Natural/immunology
• Male
• Middle Aged