Immunogenic cell death induced by anticancer chemotherapy is characterized by a series of molecular hallmarks that include the exodus of high-mobility group box 1 protein (HMGB1) from dying cells. HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and engages Toll-like receptor4 (TLR4) on dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. The absence of HMGB1 expression by dying tumor cells exposed to anthracyclines or oxaliplatin compromises DC-dependent T-cell priming by tumor-associated antigens. Here, we show that transplantable tumors exhibiting weak expression of nuclear HMGB1 respond to chemotherapy more effectively if the treatment is combined with the local or systemic administration of a highly purified and physiochemically defined and standardized lipopolysaccharide solution, which acts as a high-potency and exclusive TLR4 agonist, called Dendrophilin (DEN). The synergistic antitumor effects mediated by the combination of chemotherapy and immunotherapy relied upon the presence of the MyD88 (myeloid differentiation primary response gene) adapter of TLR4 (but not that of the TIR-domain-containing adapter-inducing interferon-β adapter), in line with the well-characterized action of DEN on the MyD88 signaling pathway. DEN and anthracyclines synergized to induce intratumoral accumulation of interferon-γ-producing CD4+ and CD8+ T lymphocytes. Moreover, DEN could restore the immunogenicity of dying tumor cells from which HMGB1 had been depleted by RNA interference. These findings underscore the potential clinical utility of combination regimens involving immunogenic chemotherapy and certain TLR4 agonists in advanced HMGB1-deficient cancers.

/pdf/defective-immunogenic-cell-death-of-hmgb1-deficient-tumors-2iommlk5bk.pdf

Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists

The inner-core region of the lipopolysaccharide of an UDPGalNAc-4-epimerase-deficient mutant of Yersinia enterocolitica 0:3, designated as Ye75R, was investigated using methylation analysis, 1D-13C-NMR and 2D-13C-NMR and 1H-NMR, as well as 31P-NMR, fast-atom-bombardment mass spectrometry (FAB MS) and FAB MS/MS in positive and negative modes. The isolated core heptasaccharide (OS) was composed of 2 units d-glucose, 3 units ld-heptose and 1 unit each of dd-heptose and 3-deoxy-d-manno-octulosonic acid. Methylation analysis indicated that OS was highly branched with terminal location of the two glucoses and the dd-heptose unit, which was partially (to about 40%) phosphorylated at C7. These combined studies allowed us to formulate the structure of the inner core region as shown in Scheme 1.



The substitution of the 7-position of the terminally linked dd-heptose unit by phosphate could be recognized by MS characterization of permethylated dd-heptose-7-phosphate (alditol acetate) and the extent of the substitution by the ratio of the two well separated 1H signals of dd-heptose in 500-MHz 1H-NMR. Negative FAB MS of OS also indicated the presence of smaller amounts of two hexasaccharides, differing from OS in lacking either one terminal unit of d-glucose or of the terminal dd-heptose, and additionally of a pentasaccharide lacking two heptosyl units, namely the terminal dd-heptose and and the subterminal ld-heptose. The presence of the smaller oligosaccharides in the OS fraction was also recognized by the methylation analysis.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1994.tb18746.x

The inner core region of Yersinia enterocolitica Ye75R (0:3) lipopolysaccharide

Summary Ten Salmonella strains belonging to five serological groups were cultivated both at 37°C and close to their individual temperature minima at 12–14°C and the composition of their cell wall lipopolysaccharides (LPS) was compared. When grown at low temperature, the proportion of unsubstituted (free) R-LPS in the total LPS moiety increased significantly in 6 strains, whereas in the other strains, no change or even a slight decrease in the R-LPS proportion was observed as judged from the analyses by SDS-PAGE. In the immunoblot, the R-LPSs from 9 out of 10 strains showed a modified reactivity against a set of specific Salmonella R antisera (anti-Ra, anti-Rb1, anti-Rb2, anti-Rc). In most cases, the decrease in Rb 1 reactivity was paralleled by an increase in Rb2 reactivity and also by an increase in the total amount of free R-LPS. The electrophoretic mobility of free R-LPS was changed in 7 out of 10 strains, although the changes were not unidirectional. All changes occurred only in the range of the Ra-Rb1 chemotypes and no significant correlation to the serological grouping of the strains was evident. When grown at low temperature, the average number of 0repeating units was reduced in the majority of cases and in some cases, also the banding profile in SDS-PAGE in the S-LPS region was modified. The fatty acid spectra showed some changes which were in accordance with previous results, namely a decrease in the content of C-12: 0 and C-16:0 and an increase in that of C-14:0 and C-16: 1. The different influences of the growth temperature on the LPS biosynthesis of different Salmonella strains may be a result of the genetic diversity of this group of microorganisms.

The influence of low growth temperature on the amount of free R Lipopolysaccharide, on the expression of R-Core determinants and on O-Chain lengths in Salmonella S Forms

Summary Two Salmonella S-forms and two R-mutants were cultivated in complex medium supplemented with different amounts (0.5-3%) glucose. Cultivation was performed batchwise in a fermentor under aerobic conditions. With all strains investigated, the yield of bacterial mass increased with increasing concentration of glucose. In the case of three strains, the LPS content of bacteria also increased, thus achieving the aim of this investigation. The synthesis of bacterial mass and LPS did not proceed in parallel and differed from strain to strain. At optimal glucose concentration, the yield of LPS could be increased up to 250%. The chemical composition of the LPS was independent of the glucose concentration. The individual strains exhibited an identical composition with regard to lipid A and polysaccharide when cultured at different glucose concentrations. The uniformity of the molecular distribution of LPS could also be confirmed by SDS-polyacrylamide gel electrophoresis. In the S-form LPSs, also the proportion of the unsubstituted R-form LPS was not affected by the glucose concentration in the culture medium. The present results demonstrate that optimisation of the cultivation conditions with respect to the glucose concentration of the medium would be of advantage especially for Salmonella strains that are cultivated frequently.

Influence of the glucose concentration on the yield of biomass and lipopolysaccharide in Salmonella cultures.

Bacterial lipopolysaccharides—Themes and variations

Summary Lipopolysaccharide (LPS) preparations from Salmonella S-form bacteria contain, in addition to S-form LPS, variable amounts of R-form material, lacking the O-specific polysaccharide. In the present study, we investigated the R-form LPS present in 22 LPS preparations derived from different Salmonella S-form strains belonging to 8 serological groups. The R-form part of the LPSs was separated by SDS-polyacrylamide gel electrophoresis and its antigen specificity analyzed by subsequent immunobloting using Salmonella R-antisera (anti-Ra, -Rbl, -Rb2, -Rc). The results show that different R-determinants were present in one and the same LPS preparation. The pattern of reaction varied considerably among individual strains. This variation was also present among strains of the same serogroup. Approximately one half of the R-form LPSs exhibited a weak or no reaction with Ra antiserum. In contrast, almost all R-form LPSs showed a significant reaction with Rbl antiserum. The electrophoretic mobility of the R-form material was very similar, exhibiting only minor differences among the different LPS preparations. In most cases, migration was similar to that of authentic Salmonella Ra-LPS; in some cases, the migration was somewhat faster resembling that of Rb1-LPS.

Immunoblot analysis of the R-form lipopolysaccharide from Salmonella S forms.

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Immunoblot analysis of the R-form lipopolysaccharide from Salmonella S forms.