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Natural killer cell-mediated ADCC in SARS-CoV-2-infected individuals and vaccine recipients.

ABSTRACT: COVID-19, caused by SARS-CoV-2, has emerged as a global pandemic. While immune responses of the adaptive immune system have been in the focus of research, the role of NK cells in COVID-19 remains less well understood. Here, we characterized NK cell-mediated SARS-CoV-2 antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 spike-1 (S1) and nucleocapsid (NC) protein. Serum samples from SARS-CoV-2 resolvers induced significant CD107a-expression by NK cells in response to S1 and NC, while serum samples from SARS-CoV-2-negative individuals did not. Furthermore, serum samples from individuals that received the BNT162b2 vaccine induced strong CD107a expression by NK cells that increased with the second vaccination and was significantly higher than observed in infected individuals. As expected, vaccine-induced responses were only directed against S1 and not against NC protein. S1-specific CD107a responses by NK cells were significantly correlated to NK cell-mediated killing of S1-expressing cells. Interestingly, screening of serum samples collected prior to the COVID-19 pandemic identified two individuals with cross-reactive antibodies against SARS-CoV-2 S1, which also induced degranulation of NK cells. Taken together, these data demonstrate that antibodies induced by SARS-CoV-2 infection and anti-SARS-CoV-2 vaccines can trigger significant NK cell-mediated ADCC activity, and identify some cross-reactive ADCC-activity against SARS-CoV-2 by endemic coronavirus-specific antibodies.

SUBMITTER: Hagemann K

PROVIDER: S-EPMC9087393 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Natural killer cell-mediated ADCC in SARS-CoV-2-infected individuals and vaccine recipients.

Hagemann Kerri K Riecken Kristoffer K Jung Johannes M JM Hildebrandt Heike H Menzel Stephan S Bunders Madeleine J MJ Fehse Boris B Koch-Nolte Friedrich F Heinrich Fabian F Peine Sven S Schulze Zur Wiesch Julian J Brehm Thomas T TT Addo Marylyn M MM Lütgehetmann Marc M Altfeld Marcus M

European journal of immunology 20220422 8

COVID-19, caused by SARS-CoV-2, has emerged as a global pandemic. While immune responses of the adaptive immune system have been in the focus of research, the role of NK cells in COVID-19 remains less well understood. Here, we characterized NK cell-mediated SARS-CoV-2 antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 spike-1 (S1) and nucleocapsid (NC) protein. Serum samples from SARS-CoV-2 resolvers induced significant CD107a-expression by NK cells in response to S1 and NC, whil ...[more]

PMID: 35416291

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Project description:Ovarian cancer is the deadliest gynecologic cancer. Although human epidermal growth factor receptor-2 (HER2) overexpression, a poor prognostic molecular marker in ovarian cancer, is found in almost 30% of ovarian cancer cases, there are no established therapies for HER2-overexpressing ovarian cancer. In this study, we investigated the efficacy of combined samfenet, a biosimilar compound of trastuzumab, and natural killer (NK) cells in preclinical model of HER2-overexpressing ovarian cancer. Firstly, we screened the HER2 expression in three ovarian cancer cell lines and eight ovarian cancer patient-derived tumor xenograft (PDTX) samples. Then, immunohistochemistry and silver in situ hybridization (SISH) were performed following clinical criteria. HER2-overexpressing cells exhibited the highest sensitivity to samfenet compared with low-HER2-expressing cells. In addition, the combination of samfenet with natural killer (NK) cells resulted in significantly enhanced sensitivity to HER2-overexpressing cells and showed a significant antitumor effect on PDTX mice compared with monotherapy. It is known that anti-HER2-humanized IgG1 monoclonal antibodies, including trastuzumab, induce antibody-dependent cellular cytotoxicity (ADCC). Consequently, the combination of samfenet with NK cells demonstrated NK cell-mediated ADCC, as confirmed using an in vitro NK cytotoxicity assay and in vivo antitumor efficacy. A transferase dUTP nick end labeling (TUNEL) assay using xenografted tumors further supported the ADCC effects based on the increase in the number of apoptotic cells in the combination group. Furthermore, high HER2 expression was associated with shorter progression-free survival and overall survival based on public mRNA expression data. In this study, we demonstrated that the combination of samfenet and NK cell therapy could be a promising treatment strategy for patients with HER2-overexpressing ovarian cancer, through ADCC effects. Therefore, this study supports a rationale for further clinical studies of the combination of samfenet and NK cells as a therapy for patients with HER2-overexpressing ovarian cancer.

Project description:ObjectivesUnderlying medical conditions are critical risk factors for COVID-19 susceptibility and its rapid clinical manifestation. Therefore, the preexisting burden of non-communicable diseases (NCDs) makes the preparedness for COVID-19 more challenging for low- and middle-income countries (LMICs). These countries have relied on vaccination campaigns as an effective measure to tackle COVID-19. In this study, we investigated the impact of comorbidities on humoral antibody responses against the specific receptor-binding domain (RBD) of SARS-CoV2.MethodsA total of 1005 patients were selected for the SARS-CoV-2 specific immunoglobulin G (IgG1, IgG2, IgG3, and IgG4 subclasses) and total antibody (TAb) tests (IgG and IgM), of which 912 serum samples were ultimately selected based on the specimen cutoff analyte value. Patients with multimorbidity (N = 60) were recruited for follow-up studies from the initial cohort, and their immune response (IgG and TAb) was measured at multiple time points after the second dose of vaccination. Siemens Dimension Vista SARS-CoV-2 IgG (CV2G) and SARS-CoV-2 TAb assay (CV2T) were used to carry out the serology test.ResultsOut of a total of 912 participants, vaccinated individuals (N = 711) had detectable antibody responses up to 7-8 months. The synergistic effect of natural infection and vaccine response was also studied. Participants with breakthrough infections (N = 49) mounted a greater antibody response compared to individuals with normal vaccination response (N = 397) and those who were naturally infected before receiving the second dose of vaccine (N = 132). Investigation of the impact of comorbidities revealed that diabetes mellitus (DM) (N = 117) and kidney disease (N = 50) had a significant negative impact on the decline of the humoral antibody response against SARS-CoV-2. IgG and TAb declined more rapidly in diabetic and kidney disease patients compared to the other four comorbid groups. Follow-up studies demonstrated that antibody response rapidly declined within 4 months after receiving the second dose.ConclusionThe generalized immunization schedule for COVID-19 needs to be adjusted for high-risk comorbid groups, and a booster dose must be administered early within 4 months after receiving the second dose.

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Natural killer cell-mediated ADCC in SARS-CoV-2-infected individuals and vaccine recipients.

Publications

Natural killer cell-mediated ADCC in SARS-CoV-2-infected individuals and vaccine recipients.

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