Potential Role of NK Cells in the Induction of Immune Responses: Implications for NK Cell–Based Immunotherapy for Cancers and Viral Infections

Takahashi, Hiroshi; Deng, Xuewen; Dewan, Zahidunnabi; Fujimoto, Shigeyoshi; Yamamoto, Naoki

doi:10.1080/08830180801911743

Cited by 87 publications

(81 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, NK cell depletion was transient regardless of antibody status or quartile, with CD16 + CD56 + cell counts being similar across strata by 3–6 months after each treatment course. Finally, the reduced alemtuzumab effect on NK cells caused by ADA is not clinically adverse, given that CD16 + CD56 + NK cells are a crucial component of the innate immune system and are known to have important immune surveillance effects 51, 52, 53.…”

Section: Discussionmentioning

confidence: 99%

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

Richards

Surks

et al. 2018

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryAlemtuzumab, a humanized anti‐CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12 or 24 mg/day of alemtuzumab in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart. Serum concentrations of alemtuzumab peaked on the last day of dosing in each course and mostly fell below the limit of quantitation by day 30. Alemtuzumab rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post‐treatment. Approximately 40 and 80% of patients had total lymphocyte counts, reaching the lower limit of normal by 6 and 12 months after each course, respectively. The clearance of alemtuzumab is dependent on circulating lymphocyte count. A majority of treated patients tested positive for anti‐alemtuzumab antibodies, including inhibitory antibodies, during the 2‐year studies, and a higher proportion of patients tested positive in course 2 than in course 1. The presence of anti‐alemtuzumab antibody appeared to be associated with slower clearance of alemtuzumab from the circulation but had no impact on the pharmacodynamics. No effects of age, race or gender on the pharmacokinetics or pharmacodynamics were observed. Together, the pharmacokinetics, pharmacodynamics and immunogenicity results support the continued development and use of alemtuzumab for the treatment of MS, and probably explain its sustained effects beyond the dosing interval.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

Richards

Surks

et al. 2018

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…NK cells are known to participate in surveillance and elimination of tumor cells through their cytolytic activity and production of cytokines that affect other components of the innate and adaptive immune systems (44). Cytolytic activity of NK cells against tumors cells is typically not antigen-dependent but may involve alternative receptor-mediated recognition of "stress-induced" ligands commonly expressed on tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Burdelya

Brackett

Kojouharov

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

175

View full text Add to dashboard Cite

Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.breast cancer | colon cancer | neutrophils | natural killer cells | Salmonella T oll-like receptors (TLRs) recognize and are activated by specific patterns in molecules that are produced by a broad range of microbial pathogens but are not present in host molecules. Activation of TLRs by these pathogen-associated molecular patterns leads to induction of infection-fighting innate immune responses (1). Various TLR agonists have been considered for multiple clinical applications, including cancer immunotherapy (2-4), and one, the TLR7 agonist imiquimod, is approved for topical treatment of basal cell carcinoma (5).Although signaling pathways induced by different TLRs all result in mobilization of an innate immune response and involve activation of nuclear factor kappa B (NF-κB), the key regulator of immunity (6, 7), TLR5 is a particularly attractive candidate for therapeutic targeting for several reasons. First, bacterial flagellin, the natural ligand of TLR5, was found to have strong radioprotective effects in rodents and nonhuman primates (8). CBLB502 is a rationally designed derivative of Salmon...

show abstract

“…Basically, normal cells express MHC class I molecules, whereas aberrant cells such as cancer cells extinguish the expression of MHC class I molecules on themselves [55] . This phenomenon was especially observed in pancreatic [56] , cervical [57] , breast [58] , prostatic [59] , and penile cancer PBMCs from each time point were extracted and co-cultured with monoclonal antibodies against CD3 and CD28 to measure IFN-g and IL-2 production levels in each supernatant.…”

Section: Hyperthermia Enhances Immune Systems In Response To Cancermentioning

confidence: 99%

“…These cancer antigens are recognized by DCs for T-cellbased cancer-specific immune responses. Additionally, activated NK cells secrete cytokines including IFN-γ and IL-2 to enhance acquired immune responses with immunoglobulin production from B-cells and activation of T-cells [55,61] . This perception leads to the conclusion that increasing the function of NK cells by hyperthermia could be expected to result in the augmentation not only of nonspecific anticancer immune reactions regulated by NK cells but also of specific anticancer immune reactions regulated by T-cells and DCs.…”

Section: Hyperthermia Enhances Immune Systems In Response To Cancermentioning

confidence: 99%

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

Yagawa¹,

Tanigawa²,

Kobayashi³

et al. 2017

JCMT

View full text Add to dashboard Cite

Hyperthermia is a type of medical modality for cancer treatment using the biological effect of artificially induced heat. Even though the intrinsic effects of elevated body temperature in cancer tissues are poorly understood, increasing the temperature of the body has been recognized as a popular therapeutic method for tumorous lesions as well as infectious diseases since ancient times. Recently accumulated evidence has shown that hyperthermia amplifies immune responses in the body against cancer while decreasing the immune suppression and immune escape of cancer. It also shows that hyperthermia inhibits the repair of damaged cancer cells after chemotherapy or radiotherapy. These perceptions indicate that hyperthermia has potential for cancer therapy in conjunction with immunotherapy, chemotherapy, radiotherapy, and surgery. Paradoxically, the anticancer effect of hyperthermia alone has not yet been adequately exploited because deep heating techniques and devices to aggregate heat effects only in cancer tissues are difficult in practical terms. This review article focuses on the current understanding concerning cancer immunity and involvement of hyperthermia and the innate and adoptive immune system. The potential for combination therapy with hyperthermia and chemotherapy, radiotherapy, and surgery is also discussed. Key words:Hyperthermia, cancer immunity, chemosensitizer, radiosensitizer, combination cancer therapy, hyperthermic intraoperative peritoneal chemotherapy ABSTRACTArticle history:

show abstract

Potential Role of NK Cells in the Induction of Immune Responses: Implications for NK Cell–Based Immunotherapy for Cancers and Viral Infections

Cited by 87 publications

References 64 publications

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

Contact Info

Product

Resources

About