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Updated: Aug 13, 2026
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Integrated transcriptional-phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in
Darawan Rinchai1, Elena Verzoni2, Veronica Huber3
1Cancer Research Department, Sidra Medicine, Doha, Qatar.
Background:
The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms.
Methods:
We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid-derived suppressor (MDSC)-like cells were generated from CD14+ monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib.
Results:
Pazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD-1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune-effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC-mediated suppression, rather than a direct effect on NK and T cells.
Conclusions:
The marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB.
Insights
Antiangiogenic pazopanib reshapes immune cells in metastatic renal cell carcinoma (mRCC) patients, decreasing suppressive cells and increasing effector cells. This transient immunomodulation suggests pazopanib as a preconditioning strategy to enhance cancer immunotherapy efficacy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint blockade (ICB) combined with standard therapies is crucial for overcoming resistance in cancers like metastatic renal cell carcinoma (mRCC).
- Understanding the immunomodulatory effects of antiangiogenic agents is key to designing effective multidrug schedules for cancer immunotherapy.
Purpose of the Study:
- To elucidate the immunomodulatory effects of the antiangiogenic agent pazopanib in mRCC patients.
- To assess the prognostic implications of pazopanib's immunomodulatory effects using The Cancer Genome Atlas (TCGA) RCC cohort.
- To investigate the in vitro effects of pazopanib on natural killer (NK) cells, T cells, and myeloid-derived suppressor cells (MDSCs).
Main Methods:
- Longitudinal analysis of immune cell subsets and transcriptional activity in nine mRCC patients over six months.
- Transcriptomic analysis of the TCGA RCC cohort (N=571) to correlate findings with prognosis.
- In vitro assessment of pazopanib's effects on NK cells, T cells, and generated MDSC-like cells.
Main Results:
- Pazopanib rapidly altered immune cell frequencies and activity, decreasing MDSCs and regulatory T cells while increasing cytotoxic T and NK effector cells.
- Observed immunomodulation, characterized by enhanced immune-effector function transcripts, was transient, peaking at three months.
- Intratumoral expression of an MDSC signature (MDSC INT) was significantly associated with poor prognosis in RCC patients.
- In vitro studies suggested pazopanib primarily inhibits MDSC-mediated suppression rather than directly affecting NK and T cells.
Conclusions:
- Pazopanib induces a marked but transient immunomodulation in mRCC patients.
- The peak immunomodulatory effect at three months supports using antiangiogenics like pazopanib as a preconditioning strategy.
- This preconditioning approach may enhance the efficacy of immune checkpoint blockade (ICB) in cancer immunotherapy.
