IgG4 induces tolerogenic M2-like macrophages and correlates with disease progression in colon cancer.

IgG4 subclass antibodies are expressed in alternative Th2 environments featuring high IL-10 expression, including several solid tumors such as melanoma. To induce tolerance, allergen immunotherapy mediates antibody class switching from pro-inflammatory IgE to anti-inflammatory IgG4. We previously reported that IgG4 drives allergic M2 macrophages toward tolerogenic states. Here we assessed the roles of IgG4 and macrophage activation in colorectal cancer (CRC). In this observer-blinded, case-control study, we analyzed total circulating serum IgE, IgG1 and IgG4 levels in CRC (n = 38) patients with (n = 13, TxNxM1) or without (n = 25, TxNxM0) metastasis, and in healthy donors (n = 21). Primary cultures of circulating monocyte-derived macrophages from healthy controls and CRC patients were further evaluated in their responses to stimulation with IgG1 or IgG4. We found higher absolute serum levels of IgG4 in patients with CRC. IgG4 enabled polarization of macrophages derived from CRC patients and healthy controls into alternatively-activated tolerogenic M2b phenotypes. IgG4-stimulated M2 macrophages were characterized by lower surface CD206, CD163, CD14, and CD11b expression and higher CCL-1, IL-10, and IL-6 production. IgG4 was less potent that IgG1 in triggering antibody-dependent cell-mediated phagocytosis (ADCP) of cancer cells. Further, higher z-normalized IgG4/-IgE sera level ratios correlated with the presence of metastasis (p = .0247 and p = .0009, respectively) in CRC patients. High IgG4 in CRC synergizes with macrophages in shaping an immunosuppressive microenvironment and impairs anti-cancer effector cell functions. The shift of serum IgG4/IgE ratios toward enhanced tolerance induction in metastatic disease indicates a role for high IgG4 in disease progression and poor prognostic outcome.

Self-reported need for psychotherapy predicts interferon-induced depression in hepatitis C: stratification for interferon-free treatment.

BACKGROUND: Interferon (IFN)-induced depression occurs in approximately 30% of chronic hepatitis C (CHC) patients undergoing pegylated (PEG)-IFN-based antiviral therapy. While IFN-free therapy has been developed, it is not accessible to all CHC patients due to the high costs of treatment. This study evaluated the Assessment of Demand for Additional Psychological Treatment (ADAPT) questionnaire as a screening tool for patients at risk of IFN-induced depression, in order to identify patients who may uniquely benefit from IFN-free regimens. METHODS: In this prospective study, consecutive patients being treated for CHC with PEG-IFN-based antiviral therapy were examined for the occurrence of depression during a 12-week treatment period. Using univariate and multivariate regression models, the value of the ADAPT questionnaire, in comparison to the Hospital Anxiety and Depression Scale (HADS), and the patients' psychiatric history was analysed. RESULTS: A total of 103 patients (59% male; median age 42) were included, of whom 25% (26/103) developed IFN-induced depression during the study period. HADS-Depression (D) subscale (OR=1.187, P=0.003; area under the curve [AUC]=0.690) and ADAPT-Psychotherapy (PT) subscale (OR=1.020, P=0.006; AUC=0.695) showed the highest accuracy for identification of patients at risk for depression. A HADS-D score of ≥7 and an ADAPT-PT score of ≥37.8 showed a similar sensitivity (61.5% versus 57.7%), whereas ADAPT-PT showed a more favourable specificity (68.9% versus 77.4%). CONCLUSIONS: The ADAPT-PT subscale effectively identifies patients at risk for IFN-induced depression and should therefore be taken into account when allocating patients to IFN-free antiviral treatment regimens.