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Blockade of IL-1b and PD-1 with combination chemotherapy reduces systemic myeloid suppression in metastatic pancreatic cancer with heterogeneous effects in the tumor

ABSTRACT: Clinical and translational results from a phase Ib trial testing whether IL-1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal anti-tumor T cell responses to PD-1 blockade.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267814 | GEO | 2024/07/01

REPOSITORIES: GEO

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Project description:TSLP pathway blockade is a potential strategy for asthma treatment, as TSLP modulates cytokine production by mast cells and regulates the activation of dendritic cells (DCs), which prime the differentiation of naM-CM-/ve T cells into inflammatory Th2 cells. To assess the effect of TSLPR blockade on the development of allergic inflammation and bronchoconstriction in Cynomolgus monkeys after Ascaris suum allergen challenge. Antibodies against human TSLPR were generated and confirmed to be cross-reactive to cynomolgus. Animals were dosed weekly with either vehicle (n=8) or TSLPR HuMAb (n=8) for 6 weeks and their responses to A.Suum challenge at baseline, week 2 and week 6 were assessed. Antibody-treated animals showed reduced bronchoalveolar lavage (BAL) eosinophil counts (p=0.04), reduced lung resistance (RL) area under the curve (p=0.04), and reduced IL-13 cytokine levels in BAL fluid (p=0.03) in response to challenge at 6 weeks compared to vehicle-treated animals. To understand the molecular changes underlying these differences, BAL fluid samples pre- and post-challenge were profiled using microarrays. Genes up-regulated by allergen challenge overlapped strongly with 11 genes up-regulated in DCs when stimulated by TSLP (TSLP-DC signature). The number of genes differentially expressed in response to challenge was reduced in aTSLPR-treated animals after 6 weeks relative to vehicle-treated animals. Expression of the TSLP-DC gene signature was also significantly reduced in aTSLPR-treated animals (p = 0.05). These results demonstrate promising efficacy for TSLPR blockade in an allergen challenge model where TSLP activation of DCs may play a key role. Animals were dosed weekly with either vehicle (n=8) or TSLPR HuMAb (n=8) for 6 weeks and their responses to A.Suum challenge at baseline, week 2 and week 6 were assessed. One monkey in the aTSLPR-treated group expired during the study for reasons not linked to drug safety and tolerability. BAL fluid samples for all animals were subject to gene expression profiling for pre-challenge, 8h and 24h post-challenge timepoints, at baseline, week 2 and week 6. This amounted to a total of 135 microarrays. Data from 8 animals were excluded as outliers, determined by PCA.

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Blockade of IL-1b and PD-1 with combination chemotherapy reduces systemic myeloid suppression in metastatic pancreatic cancer with heterogeneous effects in the tumor

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