42 research outputs found
31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two
Background
The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.
Methods
We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.
Results
First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001).
Conclusions
In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival
Microbial Transformations of Aryltetralone and Aryltetralin Lignans by Cunninghamella echinulata and Beauveria bassiana
Microbiological transformation of the aryltetralone lignan (-)-8'-epi-aristoligone (1) with Cunninghamella echinulata ATCC 10028B afforded two known natural lignans, (-)-holostyligone (3) and (-)-arisantetralone (4). Incubation of the aryltetralin lignan (-)-isogalbulin (2), obtained by chemical transformation of 1, with C. echinulata ATCC 10028B afforded the known lignan aryltetralol (5) and seven new metabolites, (-)-8-hydroxylsogalbulin (6), (-)-7-methoxyisogalbulin (7), (-)-4'-O-demethyl-8-hydroxyisogalbulin (8), (-)-7-methoxy-8-hydroxyisogalbulin (9), (-)4'-O-demethyl-7-methoxyisogalbulin (10), (-)-4',5-O-didemethylcyclogalgravin (11), and (-)-4'-O-demethylcyclogal-gravin (12). When 2 was subjected to biotransformation with Beauveria bassiana ATCC 7159, (-)-8-hydroxyisogalbulin (6) was the only isolable product. The structures of all new compounds were established by detailed analysis of their spectroscopic data.Conselho Nacional de Desenvolvimento CientÃfico e Tecnológico (CNPq
Microbial transformations of Aryltetralone and Aryltetralin Lignans by Cunninghamella echinulata and Beauveria bassiana
Microbiological transformation of the aryltetralone lignan (−)-8′-epi-aristoligone (1) with Cunninghamella echinulata ATCC 10028B afforded two known natural lignans, (−)-holostyligone (3) and (−)-arisantetralone (4). Incubation of the aryltetralin lignan (−)-isogalbulin (2), obtained by chemical transformation of 1, with C. echinulata ATCC 10028B afforded the known lignan aryltetralol (5) and seven new metabolites, (−)-8-hydroxyisogalbulin (6), (−)-7-methoxyisogalbulin (7), (−)-4′-O-demethyl-8-hydroxyisogalbulin (8), (−)-7-methoxy-8-hydroxyisogalbulin (9), (−)-4′-O-demethyl-7-methoxyisogalbulin (10), (−)-4′,5-O-didemethylcyclogalgravin (11), and (−)-4′-O-demethylcyclogalgravin (12). When 2 was subjected to biotransformation with Beauveria bassiana ATCC 7159, (−)-8-hydroxyisogalbulin (6) was the only isolable product. The structures of all new compounds were established by detailed analysis of their spectroscopic data.Conselho Nacional de Desenvolvimento CientÃfico e Tecnológico (CNPq
Thielavialides A–E, <i>Nor</i>-Spiro-azaphilones, and a Bis-spiro-azaphilone from Thielavia sp. PA0001, An Endophytic Fungus Isolated from Aeroponically Grown Physalis alkekengi
Four new <i>nor</i>-spiro-azaphilones,
thielavialides A–D (<b>1</b>– <b>4</b>),
a new bis-spiro-azaphilone, thielavialide E (<b>5</b>), together
with pestafolide A (<b>6</b>), were isolated from the endophytic
fungal strain, Thielavia sp. PA0001,
occurring in the healthy leaf tissue of aeroponically grown Physalis alkekengi. The structures and relative configurations
of <b>1</b>–<b>5</b> were established on the basis
of their MS and NMR data. Possible biosynthetic pathways to thielavialides
A–E (<b>1</b>– <b>5</b>) from pestafolide
A (<b>6</b>), some involving a Favorskii-like rearrangement,
are proposed
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Semi-synthesis and cytotoxicity evaluation of pyrimidine, thiazole, and indole analogues of argentatins A–C from guayule (Parthenium argentatum) resin
Argentatins A–C (1–3), the major cycloartane-type triterpenoids of guayule resin, a byproduct of commercial rubber production, were converted into their pyrimidine (7–12), thiazole (13–15), and indole (16–18) analogues by a molecular hybridization approach. The cytotoxic activities of these fused heterocyclic analogues 7–18 were compared with those of argentatins A–C (1–3) against a panel of three sentinel human cancer cell lines [NCI-H460 (non-small cell lung), MCF-7 (breast adenocarcinoma), and SF-268 (central nervous system glioma)], and normal human fibroblast (WI-38) cells. The cytotoxicity data suggest that the pyrimidine analogues 7 and 8 (derived from 1), 9 and 10 (derived from 2), and 12 (derived from 3) had significantly enhanced activity compared to the parent compounds or their thiazole (13–15) and indole (16–18) analogues. These findings indicate that triterpenoid constituents of guayule resin may be exploited to obtain value-added products with potential applications in anticancer drug discovery.12 month embargo; published: 17 January 2022This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]