Pazopanib induces dramatic but transient contraction of myeloid suppression compartment in favor of adaptive immunity

Rinchai, D.; Verzoni, E.; Huber, V.; Cova, A.; Squarcina, P.; Cecco, L. D.; Braud, F. d.; Ratta, R.; Dugo, M.; Lalli, L.; Vallacchi, V.; Rodolfo, M.; Roelands, J.; Castelli, C.; Chaussabel, D.; Procopio, G.; Bedognetti, D.; Rivoltini, L.

doi:10.1101/2020.05.01.071613

bioRxiv · 10.1101/2020.05.01.071613

Pazopanib induces dramatic but transient contraction of myeloid suppression compartment in favor of adaptive immunity

Rinchai, D.·Verzoni, E.·Huber, V.·Cova, A.·Squarcina, P.·Cecco, L. D.·Braud, F. d.·Ratta, R.·Dugo, M.·Lalli, L.·Vallacchi, V.·Rodolfo, M.·Roelands, J.·Castelli, C.·Chaussabel, D.·Procopio, G.·Bedognetti, D.·Rivoltini, L.

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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.

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Rinchai, D., Verzoni, E., Huber, V., Cova, A., Squarcina, P., Cecco, L. D., Braud, F. d., Ratta, R., Dugo, M., Lalli, L., Vallacchi, V., Rodolfo, M., Roelands, J., Castelli, C., Chaussabel, D., Procopio, G., Bedognetti, D., Rivoltini, L.. 2020-05-01. Pazopanib induces dramatic but transient contraction of myeloid suppression compartment in favor of adaptive immunity. https://doi.org/10.1101/2020.05.01.071613

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