The selective adsorption of a corrosive gas, SO 2 , into two microporous pillared paddle-wheel frameworks M(bdc)(ted) 0.5 [M = Ni, Zn; bdc = 1,4-benzenedicarboxylate; ted = triethylenediamine] is studied by volumetric adsorption measurements and a combination of in-situ infrared spectroscopy and ab initio density functional theory (DFT) calculations. The uptake of SO 2 in M(bdc)(ted) 0.5 at room temperature is quite significant, 9.97 mol/kg at 1.13 bar. The major adsorbed SO 2 molecules contributing to the isotherm measurements are characterized by stretching bands at 1326 and 1144 cm -1 . Theoretical calculations including van der Waals interactions (based on vdW-DF) suggest that two adsorption configurations are possible for these SO 2 molecules. One geometry involves an SO 2 molecule bonded through its sulfur atom to the oxygen atom of the paddle-wheel building unit and its two oxygen atoms to the C-H groups of the organic linkers by formation of hydrogen bonds. Such a configuration results in a distortion of the benzene rings, which is consistent with the experimentally observed shift of the ring deformation mode. In the other geometry, SO 2 establishes hydrogen bonding with -CH 2 group of the ted linker through its two oxygen atoms simultaneously. The vdW-DF-simulated frequency shifts of the SO 2 stretching bands in these two configurations are similar and in good agreement with spectroscopically measured values of physisorbed SO 2 . In addition, the IR spectra reveal the presence of another minor species, characterized by stretching modes at 1242 and 1105 cm -1 and causing significant perturbations of MOFs vibrational modes (CH x and carboxylate groups). This species is more strongly bound, requiring a higher temperature (~150 °C) to remove it than for the main physisorbed species. The adsorption configurations of SO 2 into M(bdc)(ted) 0.5 derived by infrared spectroscopy and vdW-DF calculations provide the initial understanding to develop microporous metal organic frameworks materials based on paddlewheel secondary-building units for SO 2 removal in industrial processes.

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the anti-tumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer-induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice restored MPL/TDCM-induced protection in mice with B cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell-produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4–mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Our previous studies demonstrated a toll-like receptor 4 (TLR4) and C-type lectin receptor (CLR; Mincle/MCL) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits peritoneal tumor growth and ascites development through a mechanism dependent upon B-1a cellproduced natural IgM, complement, and phagocytes. In the current study, we investigated the requirement for TLR4 and Fc receptor common γ chain (FcRγ), required for Mincle/MCL signaling, in the MPL/TDCM-elicited response. MPL/TDCM significantly increased macrophages and Ly6C hi monocytes in the peritoneal cavity of both TLR4 −/− and FcRγ −/− mice, suggesting redundancy in the signals required for monocyte/macrophage recruitment. However, B1 cell activation, antibody secreting cell (ASC) differentiation, and tumor-reactive IgM production was defective in TLR4 −/− , but not FcRγ −/− mice. TRIF was required for production of IgM reactive against tumor-and mucin-related antigens, but not phosphorylcholine, whereas TLR4 was required for production of both types of reactivities. Consistent with this, B1 cells lacking TLR4 or TRIF did not proliferate or differentiate into tumor-reactive IgM-producing cells in vitro and did not reconstitute MPL/TDCM-dependent protection against peritoneal carcinomatosis in CD19 −/− mice. Our results indicate a TLR4/TRIF-dependent pathway is required by B1 cells for MPL/TDCM-elicited production of protective tumor-reactive natural IgM. The dependency on TRIF signaling for tumor-reactive, but not phosphorylcholine-reactive, IgM production reveals unexpected heterogeneity in TLR4-dependent regulation of natural IgM production, thereby highlighting important differences to consider when designing vaccines/therapies targeting these specificities.

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Our previous study demonstrated a toll-like receptor (TLR) and Ctype lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development following TA3-Ha and EL4 challenge through a mechanism dependent upon B-1a cell-produced natural IgM and complement. In the current study, we investigated additional players in the MPL/TDCM-elicited response. MPL/TDCM treatment rapidly increased type I IFN levels in the peritoneal cavity along with myeloid cell numbers, including macrophages and Ly6C hi monocytes. Type I IFN receptor (IFNAR1 -/-) mice produced tumor-reactive IgM following MPL/TDCM treatment, but failed to recruit Ly6C + monocytes and were not afforded protection during tumor challenges. Clodronate liposome depletion of phagocytic cells, as well as targeted depletion of Ly6C + cells, also ablated MPL/TDCM-induced protection. Cytotoxic mediators known to be produced by these cells were required for effects. TNF was required for effective TA3-Ha killing and nitric oxide was required for EL4 killing. Collectively, these data reveal a model whereby MPL/TDCM-elicited anti-tumor effects strongly depend on innate cell responses, with B-1a cell-produced tumor-reactive IgM and complement pairing with myeloid cell-produced cytotoxic mediators to effectively eradicate tumors in the peritoneal cavity.