NCI-H460 gene expression analysis after in vivo treatment with anti-PD1 antibody
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ABSTRACT:
PROVIDER: PRJNA866142 | ENA |
REPOSITORIES: ENA
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Project description:Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 axis have made a breakthrough in the treatment of non-small cell lung cancer (NSCLC). However, a paradoxical boost in tumor growth was reported in a fraction of NSCLC patients after ICIs administration: a novel pattern of cancer progression defined “hyperprogressive disease” (HPD). Because the mechanism of HPD onset has not completely elucidated yet, this study aimed at investigating the cellular and molecular bases of this clinical phenomenon. Pre-treatment histological samples obtained from NSCLC patients were evaluated by immunohistochemistry (IHC) for immune cell infiltrate. Tissue samples from all patients with HPD showed tumor-infiltration by M2-like macrophages. To validate these findings in preclinical models, we utilized athymic nude mice that, lacking T-cells that may cloud the results, represent a suitable model to evaluate the role of macrophages in determining HPD. Immunodeficient mice were injected with human NSCLC NCI-H460 cell line, treated with anti-PD-1 antibody and tumor growth was evaluated over time. Anti-PD-1 treated H460 tumor-bearing mice showed HPD-like tumor growth as well as an increase in macrophage infiltration compared to control group. Interestingly, in these in vivo models, HPD-like growth, triggered by anti-PD-1 treatment, was dependent of anti-PD-1 antibody Fc domain. These results suggest that macrophages are the major players in HPD development and that FcR engagement on macrophages may determine a functional reprogramming of these immune cells toward a more aggressive and pro-tumorigenic phenotype, eventually inducing HPD.
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Project description:The libraries contained in this experiment come from independent growths of cell line NCI-H460, a male large cell lung carcinoma. They are stranded PE101 Illumina Hi-Seq RAMPAGE libraries from rRNA-depleted Total RNA > 200 nucleotides in size. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODE_Data_Use_Policy_for_External_Users_03-07-14.pdf
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