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Transcriptome Profiling and Characterization of Peritoneal Metastasis Ovarian Cancer Xenografts in Humanized Mice

ABSTRACT: Background: Although immunotherapy has not yet been as successful in ovarian cancer (OC), it remains a potential therapeutic strategy. Preclinical models of OC are necessary to evaluate the efficacy of immuno-oncology (IO) drugs targeting human cancer and immune components but have been underutilized. Developing mouse models with a humanized (Hu) immune system can help understand the human immune response to IO drugs, including immune checkpoint inhibitors (ICIs), which have demonstrated limited effectiveness in OC patients. Methods: We established OC xenograft Hu-mouse models by intraperitoneally injecting luciferase-expressing SKOV-3 Luc and OVCAR-3 Luc OC cells into CD34+ Hu-mice. Tumor growth was monitored through bioluminescence imaging (BLI). We assessed the efficacy of PD-1 blockade with pembrolizumab in the SKOV-3 Luc Hu-mouse model. The immune profiles of the tumors were characterized using colorimetric immunostaining and flow cytometry. Additionally, we analyzed RNA-seq data to investigate the gene expression signature of pembrolizumab refractory tumors. Results: We confirmed tumor development in both OC cell lines within CD34+ Hu-mice. In these models, human lymphocyte and myeloid cell subsets were present in the tumors, draining lymph nodes, blood, and spleens. The SKOV-3 Luc tumor-bearing Hu-mice did not respond to pembrolizumab monotherapy. These tumors exhibited a high presence of tumor-infiltrating macrophages. Tumors in Hu-mice unresponsive to pembrolizumab showed a lower abundance of CD8+ T-cells, memory B cells, plasma cells, and a higher proportion of naïve M0 macrophages and mast cells compared to the PBS control. Furthermore, we identified 43 significantly enriched gene sets in these tumors. The differentially expressed genes (DEGs) were predominantly enriched in HDAC class I, RB1, KLF1/3, TCF21, MYD88, SMARCE1 target genes, and genes associated with epithelial-mesenchymal transition (EMT) and fibroblasts. Conclusion: Our xenograft Hu-mouse model of OC provides a valuable tool for investigating the efficacy of IO drugs. The insights gained from this model offer potential avenues to explore mechanisms of resistance to PD-1/PD-L1 blockade in OC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245913 | GEO | 2024/03/11

REPOSITORIES: GEO

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Project description:Background: Anti-PD-1 therapy has become a cornerstone of tumor immunotherapy. Over a dozen of anti-PD-1/PD-L1 antibodies have currently been marketed. However, these agents exhibit notable disparities in their characteristics and clinical performance. For instance, in the field of small cell lung cancer (SCLC) where the majority of anti-PD-1 antibodies yielded limited success, Serplulimab produced impressive survival improvements and has been approved by NMPA. The marketing authorization application has also been validated by EMA. Nevertheless, the molecular mechanism underpinning Serplulimab’s superiority over its competitors remains elusive. Methods: We characterized the difference of Serplulimab with approved PD-1/PD-L1 inhibitors such as Pembrolizumab and Nivolumab on their antibody binding features and funcations in vitro and anti-tumor activity in vivo. We also investigated the potential cellular pathways underlying the efficacy of Serplulimab in combination with other immune checkpoint inhibitors. Results: In comparison to competitors, Serplulimab robustly induces PD-1 receptor endocytosis while fostering weaker PD-1-CD28 cis interactions. This phenomenon could mitigate the dephosphorylation of CD28 by SHP2, thereby facilitating sustained and robust T cell activation. Notably, Serplulimab and Pembrolizumab exhibited similar performance in both in vitro Mixed Lymphocyte Reaction assays and in vivo efficacy studies. However, upon co-administration with anti-TIGIT or anti-LAG3, the Serplulimab-containing combination consistently demonstrated superior tumor killing efficacy compared to the Pembrolizumab-based combination. Moreover, our mechanistic investigations have unveiled that the Serplulimab combination effectively reduces tumor microenvironment Treg cell populations, augments effector and memory T cell populations, and more potently modulates genes associated with diverse facets of the immune system, surpassing the effects of the Pembrolizumab combination. Conclusions: In summary, our data underscore Serplulimab as a highly differentiated PD-1 monoclonal antibody with best-in-class therapeutic potential

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Transcriptome Profiling and Characterization of Peritoneal Metastasis Ovarian Cancer Xenografts in Humanized Mice

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