Immunization with mannosylated nanovaccines and inhibition of the immune-suppressing microenvironment sensitizes melanoma to immune checkpoint modulators

João Conniot, Anna Scomparin, Carina Peres, Eilam Yeini, Sabina Pozzi, Ana I. Matos, Ron Kleiner, Liane I.F. Moura, Eva Zupančič, Ana S. Viana, Hila Doron, Pedro M.P. Gois, Neta Erez, Steffen Jung, Ronit Satchi-Fainaro, Helena F. Florindo

Research output: Contribution to journalArticlepeer-review

Abstract

A low response rate, acquired resistance and severe side effects have limited the clinical outcomes of immune checkpoint therapy. Here, we show that combining cancer nanovaccines with an anti-PD-1 antibody (αPD-1) for immunosuppression blockade and an anti-OX40 antibody (αOX40) for effector T-cell stimulation, expansion and survival can potentiate the efficacy of melanoma therapy. Prophylactic and therapeutic combination regimens of dendritic cell-targeted mannosylated nanovaccines with αPD-1/αOX40 demonstrate a synergism that stimulates T-cell infiltration into tumours at early treatment stages. However, this treatment at the therapeutic regimen does not result in an enhanced inhibition of tumour growth compared to αPD-1/αOX40 alone and is accompanied by an increased infiltration of myeloid-derived suppressor cells in tumours. Combining the double therapy with ibrutinib, a myeloid-derived suppressor cell inhibitor, leads to a remarkable tumour remission and prolonged survival in melanoma-bearing mice. The synergy between the mannosylated nanovaccines, ibrutinib and αPD-1/αOX40 provides essential insights to devise alternative regimens to improve the efficacy of immune checkpoint modulators in solid tumours by regulating the endogenous immune response.

Original languageEnglish
Pages (from-to)891-901
Number of pages11
JournalNature Nanotechnology
Volume14
Issue number9
DOIs
StatePublished - 1 Sep 2019

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