Impaired immunogenicity after vaccination for SARS-CoV-2 in patients with gastrointestinal cancer: does tumor entity matter?

Background: SARS-CoV-2 immunogenicity in patients with gastrointestinal cancer (GI cancer) following second and third vaccination was analyzed. Methods: A total of 125 patients under active anticancer therapy or in follow-up care were included in this prospective study. Seroprevalence of SARS-CoV-2 anti-spike and surrogate neutralization antibodies (NABs) was measured. Results: Four weeks after second vaccination, adequate titers of SARS-CoV-2 anti-spike immunoglobulin G (IgG) [≥282.0 binding antibody units (BAU)/mL] were found in 62.2% of patients under treatment versus 96.3% of patients in follow-up care (P<0.01). Sufficient titers of SARS-CoV-2 surrogate NAB (≥85.0%) were found in 32.7% of patients under treatment versus 70.6% in follow-up care (P<0.01). Titers of SARS-CoV-2 anti-spike IgG were especially low in patients with colorectal cancer (CRC). For SARS-CoV-2 surrogate NAB, patients with hepatocellular carcinoma (HCC) and with pancreaticobiliary cancer showed the lowest titers (P<0.01). SARS-CoV-2 anti-spike IgG and SARS-CoV-2 surrogate NAB were associated with a correlation coefficient of 0.93. Reaching a titer of SARS-CoV-2 anti-spike IgG ≥482.0 BAU/mL, protective levels of SARS-CoV-2 surrogate NAB (≥85.0%) could be assumed. Following booster vaccination, all patients reached effective antibody titers. Conclusions: Patients with active GI cancer showed impaired immunogenicity after second SARS-CoV-2 vaccination which was overcome by booster vaccination. Our findings were tumor-related and pronounced in patients with CRC and HCC. Waning immunity over time and antibody escape phenomena by variant of concern Omicron must be considered in these especially vulnerable patients.

Mitochondrial Dysfunction Contributes to Impaired Cytokine Production of CD56bright Natural Killer Cells From Human Immunodeficiency Virus-Infected Individuals Under Effective Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection is associated with impaired natural killer (NK) cell activity, which is only incompletely restored under antiretroviral therapy. Analyzing the bioenergetics profiles of oxygen consumption, we observed that several parameters were significantly reduced in HIV+ NK cells, indicating a mitochondrial defect. Accordingly, we found HIV+ CD56bright NK cells to display a decreased mitochondrial membrane potential and mitochondrial mass. Both parameters were positively correlated with interferon gamma (IFN-γ) production of NK cells. Finally, we demonstrated that stimulation of HIV+ NK cells with MitoTEMPO, a mitochondria-targeting antioxidant, significantly improved IFN-γ production. We identified mitochondrial dysfunction as a mechanism that contributes to impaired NK cell function.

Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19.

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.

Inducible targeting of cDCs and their subsets in vivo.

Conventional dendritic cells (cDCs) are essential immune cells linking the innate and adaptive immune system. cDC depletion in mice is an important method to study the function of these cells in vivo. Here we report an inducible in vivo system for cDC depletion in which excision of a loxP flanked Stop signal enables expression of the human diphtheria toxin receptor (DTR) under the control of Zbtb46 (zDC(lSlDTR)). cDCs can be specifically depleted by combining zDC(lSlDTR) mice with a Csf1r(Cre) driver line. In addition, we show that zDC(Cre) mice can be used to produce cDC specific conditional knockout mice (Irf8, Irf4, Notch2) which lack specific subsets of cDCs.