Integrated transcriptional and phenotypic analysis of peripheral blood to capture the immunomodulating properties of pazopanib in rena; cell carcinoma patients

ABSTRACT: Background: The sequential and combination treatment with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in metastatic renal cell carcinoma (mRCC) patients has entered the clinical practice. The dissection of the molecular mechanisms governing the impact of TKIs on the immune system is critical to implement therapeutic approaches and generate biomarkers. We here investigated the immunomodulatory activity of pazopanib in peripheral blood mononuclear cells (PBMCs) of mRCC patients through an integrative genomic analysis pipeline. Results: The transcriptional analysis indicates a modulation of leukocyte functional orientation induced by pazopanib with an increase of immune effector cell subtypes and a decrease of immune suppressive populations. At the group level transcriptome profiles revealed perturbations to peak at 3 and decrease at 6 months. These included enrichments of modules associated with cytotoxic/NK (M3.6 and M8.46), plasma cells (M4.11), T cell (M4.15) and immune responses (M8.89). At individual patient level, pazopanib administration was associated with a decrease of the immunosuppressive module M9.34 in the majority of patients. Interestingly, a rapid increase of Interferon (IFN) modules (M1.2 and M3.4) was observed exclusively in patients displaying a strong enrichment in modules associated with cytotoxic/NK cells. Multicolor flow cytometry confirmed the association of pazopanib treatment with a decrease of immune suppressive cell subsets, including CD14+HLA-DRneg myeloid derived suppressor cells (MDSCs), CD14+ and CD14+PD-L1+ monocytes, CD15+ granulocytic MDSCs and CD4+CD25highFoxp3+ regulatory T cells. Concomitantly, a boost of activated CD3+PD-1dim T lymphocytes and cytotoxic CD3-CD16+CD56dim NK cells was observed. These changes were predominantly detectable after 3 months of therapy with pazopanib. Conclusions: As systems approach, pazopanib reshapes anti-tumor immunity by relieving immunosuppression and triggering cytotoxic mechanisms and IFN pathways. The peak of this immune modulation is observed after 3 months of therapy. Our data provides a strong rationale in support of combinatorial or sequential therapies based on TKIs and immunotherapy approaches and for implementing transcriptomic analysis of blood as biomarker of immune responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146163 | GEO | 2021/06/28

REPOSITORIES: GEO