Abstract
Anti-angiogenic tyrosine-kinase inhibitors (TKIs) and immune checkpoint blockade (ICB) constitute the backbone of metastatic renal cell carcinoma (mRCC) treatment. The development of the optimal combinatorial or sequential approach is hindered by the lack of comprehensive data regarding TKI-induced immunomodulation and its kinetics. Through the use of orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines, we demonstrated that the anti-angiogenic TKI pazopanib induces a dramatic and coherent reshaping of systemic immunity in mRCC patients, downsizing the myeloid-derived suppressor cell (MDSC) compartment in favor of a strong enhancement of cytotoxic T and Natural Killer (NK) cell effector functions. The intratumoral expression level of a MDSC signature here generated was strongly associated with poor prognosis in mRCC patients. The marked but transient nature of this immunomodulation, peaking at the 3rd month of treatment, provides the rationale for the use of TKIs as a preconditioning strategy to improve the efficacy of ICB.
Competing Interest Statement
EV reports personal fees for advisory boards from Pfizer, Ipsen, Novartis outside of the submitted work. No potential conflicts of interest were disclosed by the other authors.
Abbreviation List
- DC
- Dendritic cell
- iDC
- Immature dendritic cell
- mDC
- Myeloid dendritic cells
- pDC
- Plasmacytoid dendritic cells
- ICB
- Immune checkpoint blockade
- IFN
- Interferon
- IPA
- Ingenuity Pathway Analysis
- MDSC
- Myeloid derived suppressor cells
- G-MDSC
- Granulocytic Myeloid derived suppressor cells
- M-MDSC
- Monocytic Myeloid derived suppressor cells
- mRCC
- Metastatic renal cell carcinoma
- NK
- Natural killer cell
- PCA
- Principal component analysis
- PBMCs
- Peripheral blood mononuclear cells
- Tcm
- Central memory T cell
- Tem
- Effector memory T cells
- Tfh
- T follicular helper cells
- Th2 cells
- T helper 2 cells
- Th1 cells
- T helper 1 cells
- Th17 cells
- T helper 17 cells
- Tgd
- T gamma delta cells
- Treg
- Regulatory T cell
- TKI
- Tyrosine-kinase inhibitor
- VEGF
- Vascular endothelial growth factor