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. We analyzed the potential impact of preoperative and postoperative immune phenotypes and function on postoperative survival with >30 months follow-up. The surgery entailed prompt expansion of monocytic myeloid-derived suppressor cells (M-MDSC) that generated NOX2-derived reactive oxygen species (ROS). Strong induction of immunosuppressive M-MDSC after surgery predicted poor postoperative survival and coincided with reduced functionality of circulating natural killer (NK) cells. The negative impact of surgery-induced M-MDSC on survival remained significant in separate analysis of patients with PDAC. M-MDSC-like cells isolated from patients after surgery significantly suppressed NK cell function ex vivo, which was reversed by inhibition of NOX2-derived ROS. High NOX2 subunit expression within resected tumors from patients with PDAC correlated with poor survival whereas high expression of markers of cytotoxic cells associated with longer survival. The surgery-induced myeloid inflammation was recapitulated in vivo in a murine model of NK cell-dependent metastasis. Surgical stress thus induced systemic accumulation of M-MDSC-like cells and promoted metastasis of NK cell-sensitive tumor cells. Genetic or pharmacologic suppression of NOX2 reduced surgery-induced inflammation and distant metastasis in this model. We propose that NOX2-derived ROS generated by surgery-induced M-MDSC may be targeted for improved outcome after pancreatic cancer surgery.
Pancreatic cancer surgery triggered pronounced accumulation of NOX2+ myeloid-derived suppressor cells that inhibited NK cell function and negatively prognosticated postoperative patient survival. We propose the targeting of M-MDSC as a conceivable strategy to reduce postoperative immunosuppression in pancreatic cancer.
© 2024 The Authors; Published by the American Association for Cancer Research.

The presence of myenteric plexitis in the proximal resection margins is a predictive factor of early postoperative recurrence in Crohn's disease. To decipher the mechanisms leading to their formation, T-cell interactions with enteric neural cells were studied in vitro and in vivo.
T cells close to myenteric neural cells were retrospectively quantified in ileocolonic resections from 9 control subjects with cancer and 20 patients with Crohn's disease. The mechanisms involved in T-cell adhesion were then investigated in co-cultures of T lymphocytes with enteric glial cells (glia). Finally, the implication of adhesion molecules in the development of plexitis and colitis was studied in vitro but also in vivo in Winnie mice.
The mean number of T cells close to glia, but not neurons, was significantly higher in the myenteric ganglia of relapsing patients with Crohn's disease (2.42 ± 0.5) as compared with controls (0.36 ± 0.08, P = .0007). Co-culture experiments showed that exposure to proinflammatory cytokines enhanced T-cell adhesion to glia and increased intercellular adhesion molecule-1 (ICAM-1) expression in glia. We next demonstrated that T-cell adhesion to glia was inhibited by an anti-ICAM-1 antibody. Finally, using the Winnie mouse model of colitis, we showed that the blockage of ICAM-1/lymphocyte function-associated antigen-1 (LFA-1) with lifitegrast reduced colitis severity and decreased T-cell infiltration in the myenteric plexus.
Our present work argues for a role of glia-T-cell interaction in the development of myenteric plexitis through the adhesion molecules ICAM-1/LFA-1 and suggests that deciphering the functional consequences of glia-T-cell interaction is important to understand the mechanisms implicated in the development and recurrence of Crohn's disease.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Background: Aging is a natural process characterized by a progressive functional impairment and reduced capacity to respond adaptively to environmental stimuli.Idiopathic pulmonary fibrosis(IPF)has been found to increase considerably with age.Immunosenescence,oxidative stress,abnormal shortening of telomeres, apoptosis, and epigenetic changes affecting gene expression have been proposed to contribute to the aging process,and aging-associated diseases.We used oxidative stress and immune senescence to identify the relationship between aging and pulmonary fibrosis(PF).In clinical studies,the combination of methylprednisolone(MP) and cyclophosphamide(CTX) has great benefits for patients with IPF,but the mechanisms involved in aging are not well understood. Methods: : PF rat models were induced by bleomycin(BLM) and treated with MP or MP/CTX combination.Transmission electron microscope, hematoxylin and eosin (H&E) and Masson staining were used to measure the morphology of PF.Malondialdehyde(MDA),myeloperoxidase(MPO),lutathione peroxidase(GSH-PX) and superoxide dismutase(SOD) levels were determined using commercial kits.T cells were analyzed with flow cytometry. Results: : We found that the combined use of MP and CTX can reduce collagen deposition,decreased the level of MDA,while increased the level of MPO and the activities of SOD and GSH-PX.Further,MP and CTX combination inhibited T cell senescence in lung tissues, such as decreasing CD4+CD27-CD28-cells. Conclusions: : Aging was associated with PF.The combination of MP and CTX improved the degree of PF by reducing oxidative stress and inhibiting T cell senescence.These findings provide novel insights into the mechanisms by which MP and CTX combination affects PF.

h4>Background: /h4> In clinical studies, the combination of methylprednisolone (MP) and cyclophosphamide (CTX) has great benefits for patients with pulmonary fibrosis (PF), but the mechanism of improving PF is not clear. h4>Methods: /h4>: PF rat models were induced by bleomycin and treated with MP or MP/CTX combination. Transmission electron microscope, hematoxylin and eosin (HE) and Masson staining were used to measure the morphology of PF. ELISA kits were used to test inflammatory factor levels. MDA, SOD, GSH-PX levels were determined using commercial kits. α-SMA and collagen I levels were examined by western blot and immunohistochemistry. T cells were analyzed with flow cytometry. h4>Results: /h4>: We found that the combined use of MP and CTX can reduce collagen deposition, α-SMA and collagen I levels in bleomycin induced PF. Moreover, combined treatment with MP and CTX decreased the levels of MDA and inflammatory factors (TNF-α, IL-1 β and IL-6), while increased the activities of SOD and GSH-PX. Further, MP and CTX combination changed T cell types in lung tissues, such as increasing CD4 + CD25 + Foxp3 + cells. h4>Conclusions: /h4>: The combination of MP and CTX improved the degree of PF by reducing inflammation, oxidative stress and improving T cell immunity. These findings provide novel insights into the mechanisms by which MP and CTX combination affects PF.

Voltage-gated Kv1.3 and Ca2+-dependent KCa3.1 are the most prevalent K+ channels expressed by human and rat T cells. Despite the preferential upregulation of Kv1.3 over KCa3.1 on autoantigen-experienced effector memory T cells, whether Kv1.3 is required for their induction and function is unclear. Here we show, using Kv1.3-deficient rats, that Kv1.3 is involved in the development of chronically activated antigen-specific T cells. Several immune responses are normal in Kv1.3 knockout (KO) rats, suggesting that KCa3.1 can compensate for the absence of Kv1.3 under these specific settings. However, experiments with Kv1.3 KO rats and Kv1.3 siRNA knockdown or channel-specific inhibition of human T cells show that maximal T-cell responses against autoantigen or repeated tetanus toxoid stimulations require both Kv1.3 and KCa3.1. Finally, our data also suggest that T-cell dependency on Kv1.3 or KCa3.1 might be irreversibly modulated by antigen exposure.