Impact of Surgery-Induced Myeloid-derived Suppressor Cells and the NOX2/ROS Axis on Postoperative Survival in Human Pancreatic Cancer.

Unlabelled: Preclinical studies imply that surgery triggers inflammation that may entail tumor outgrowth and metastasis. The potential impact of surgery-induced inflammation in human pancreatic cancer is insufficiently explored. This study included 17 patients with periampullary cancer [pancreatic ductal adenocarcinoma (PDAC) n = 14, ampullary carcinoma n = 2, cholangiocarcinoma n = 1] undergoing major pancreatic cancer surgery with curative intent.

Presence of MDSC associates with impaired antigen-specific T cell reactivity following COVID-19 vaccination in cirrhotic patients.

Background And Aims: Cirrhosis entails high risk of serious infections and abated efficiency of vaccination, but the underlying mechanisms are only partially understood. This study aimed at characterizing innate and adaptive immune functions, including antigen-specific T cell responses to COVID-19 vaccination, in patients with compensated and decompensated cirrhosis.

Methods: Immune phenotype and function in peripheral blood from 42 cirrhotic patients and 44 age-matched healthy controls were analysed after two doses of the mRNA-based COVID-19 vaccines [BNT162b2 (Pfizer BioNTech) or mRNA-1273 (Moderna)].

Induction and subsequent decline of S1-specific T cell reactivity after COVID-19 vaccination.

We analyzed magnitude and duration of SARS-CoV-2-specific T cell responses in healthy, infection-naïve subjects receiving COVID-19 vaccines. Overlapping peptides spanning the N-terminal spike 1 (S1) domain of the spike protein triggered secretion of the T cell-derived cytokine interleukin-2 ex vivo in 94/94 whole blood samples from vaccinated subjects at levels exceeding those recorded in all 45 pre-vaccination samples. S1-specific T cell reactivity was stronger in vaccinated subjects compared with subjects recovering from natural COVID-19 and decayed with an estimated half-life of 134 days in the first six months after the 2nd vaccination.

An adjuvant-containing cDC1-targeted recombinant fusion vaccine conveys strong protection against murine melanoma growth and metastasis.

Type 1 conventional dendritic cells (cDC1) efficiently cross-present antigens that prime cytotoxic CD8 T cells. cDC1 therefore constitute conceivable targets in cancer vaccine development. We generated recombinant fusion cancer vaccines that aimed to concomitantly deliver tumor antigen and adjuvant to CD103 migratory cDC1, following intranasal administration.

Transient and durable T cell reactivity after COVID-19.

This study analyzed whole blood samples ( = 56) retrieved from 30 patients at 1 to 21 (median 9) mo after verified COVID-19 to determine the polarity and duration of antigen-specific T cell reactivity against severe acute respiratory syndrome coronavirus 2-derived antigens. Multimeric peptides spanning the entire nucleocapsid protein triggered strikingly synchronous formation of interleukin (IL)-4, IL-12, IL-13, and IL-17 ex vivo until ∼70 d after confirmed infection, whereafter this reactivity was no longer inducible. In contrast, levels of nucleocapsid-induced IL-2 and interferon-γ remained stable and highly correlated at 3 to 21 mo after infection.

Impaired SARS-CoV-2-specific T-cell reactivity in patients with cirrhosis following mRNA COVID-19 vaccination.

Background & Aims: Cirrhosis entails elevated risk of COVID-19-associated mortality. This study determined T cell-mediated and antibody reactivity against the spike 1 (S1) protein of SARS-CoV-2 among 48 patients with cirrhosis and 39 healthy controls after mRNA COVID-19 vaccination.

Methods: SARS-CoV-2-specific T-cell reactivity was measured by induced level of T cell-derived interferon-γ (IFN-γ) in blood cells stimulated with multimeric peptides spanning the N-terminal portion of S1.

Deficiency of SARS-CoV-2 T-cell responses after vaccination in long-term allo-HSCT survivors translates into abated humoral immunity.

Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological diseases are at risk of severe disease and death from COVID-19. To determine the safety and immunogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines, samples from 50 infection-naive allo-HSCT recipients (median, 92 months from transplantation, range, 7-340 months) and 39 healthy controls were analyzed for serum immunoglobulin G (IgG) against the receptor binding domain (RBD) within spike 1 (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; anti-RBD-S1 IgG) and for SARS-CoV-2-specific T-cell immunity, reflected by induction of T-cell-derived interferon-γ in whole blood stimulated ex vivo with 15-mer SI-spanning peptides with 11 amino acid overlap S1-spanning peptides. The rate of seroconversion was not significantly lower in allo-transplanted patients than in controls with 24% (12/50) and 6% (3/50) of patients remaining seronegative after the first and second vaccination, respectively.

Rapid Cytokine Release Assays for Analysis of Severe Acute Respiratory Syndrome Coronavirus 2-Specific T Cells in Whole Blood.

Background: Waning of immunoglobulin G (IgG) antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) complicates the diagnosis of past infection. The durability of T-cell memory against SARS-CoV-2 remains unclear, and most current T-cell protocols are unsuited for large-scale automation.

Methods: Whole-blood samples from 31 patients with verified past coronavirus disease 2019 (COVID-19) and 46 controls, of whom 40 received COVID-19 vaccine, were stimulated with peptides spanning the nucleocapsid (NC) or spike 1 (S1) regions of SARS-CoV-2 and analyzed for interferon γ in supernatant plasma.

Impact of IL-1β and the IL-1R antagonist on relapse risk and survival in AML patients undergoing immunotherapy for remission maintenance.

Interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, has been ascribed a role in the expansion of myeloid progenitors in acute myeloid leukemia (AML) and in promoting myeloid cell-induced suppression of lymphocyte-mediated immunity against malignant cells. This study aimed at defining the potential impact of IL-1β in the post-remission phase of AML patients receiving immunotherapy for relapse prevention in an international phase IV trial of 84 patients (ClinicalTrials.gov; NCT01347996).

NOX2-Derived Reactive Oxygen Species in Cancer.

The formation of reactive oxygen species (ROS) by the myeloid cell NADPH oxidase NOX2 is critical for the destruction of engulfed microorganisms. However, recent studies imply that ROS, formed by NOX2 myeloid cells in the malignant microenvironment, exert multiple actions of relevance to the growth and spread of neoplastic cells. By generating ROS, tumor-infiltrating myeloid cells and NOX2 leukemic myeloid cells may thus (i) compromise the function and viability of adjacent cytotoxic lymphocytes, including natural killer (NK) cells and T cells, (ii) oxidize DNA to trigger cancer-promoting somatic mutations, and (iii) affect the redox balance in cancer cells to control their proliferation and survival.

NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease.

Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly defined. To determine the role of NOX2-derived ROS in RAS-driven leukemia, double transgenic LSL-Kras × Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-Kras) were treated with N-methyl-histamine (NMH) that targeted the production of NOX2-derived ROS in leukemic cells by agonist activity at histamine H receptors.

Histamine targets myeloid-derived suppressor cells and improves the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade.

Myeloid-derived suppressor cells (MDSCs) are immature monocytes and granulocytes that impede immune-mediated clearance of malignant cells by multiple mechanisms, including the formation of immunosuppressive reactive oxygen species (ROS) via the myeloid cell NADPH oxidase (NOX2). Histamine dihydrochloride (HDC), a NOX2 inhibitor, exerts anti-cancer efficacy in experimental tumor models but the detailed mechanisms are insufficiently understood. To determine effects of HDC on the MDSC compartment we utilized three murine cancer models known to entail accumulation of MDSC, i.

Anti-Leukemic Properties of Histamine in Monocytic Leukemia: The Role of NOX2.

In patients with acute myeloid leukemia (AML), treatment with histamine dihydrochloride (HDC) and low-dose IL-2 (HDC/IL-2) in the post-chemotherapy phase has been shown to reduce the incidence of leukemic relapse. The clinical benefit of HDC/IL-2 is pronounced in monocytic forms of AML, where the leukemic cells express histamine type 2 receptors (HR) and the NAPDH oxidase-2 (NOX2). HDC ligates to HRs to inhibit NOX2-derived formation of reactive oxygen species, but details regarding the anti-leukemic actions of HDC remain to be elucidated.

Mutated NPM1 in combination with overexpression of Meis1 or Hoxa9 is not sufficient to induce acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) carrying nucleophosmin 1 (NPM1) mutations (NPMc(+)) is regarded as a separate entity of myeloid neoplasms due to its distinct biological and clinical features. However, NPMc(+) alone displays low leukemogenic activity and cooperating events appear crucial for AML to develop. Dysregulation of homeobox genes, such as HOXA9 and MEIS1, is a common transcriptional signature of NPMc(+) AML.