Polyoxazoline-Based Nanovaccine Synergizes with Tumor-Associated Macrophage Targeting and Anti-PD-1 Immunotherapy against Solid Tumors

Ana I. Matos, Carina Peres, Barbara Carreira, Liane I.F. Moura, Rita C. Acúrcio, Theresa Vogel, Erik Wegener, Filipa Ribeiro, Marta B. Afonso, Fábio M.F. Santos, Águeda Martínez-Barriocanal, Diego Arango, Ana S. Viana, Pedro M.P. Góis, Liana C. Silva, Cecília M.P. Rodrigues, Luis Graca, Rainer Jordan, Ronit Satchi-Fainaro*, Helena F. Florindo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Immune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co-delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)-β expression using a polyoxazoline (POx)-poly(lactic-co-glycolic) acid (PLGA) nanovaccine, while modulating the tumor-associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti-programmed cell death protein 1 (PD-1) can constitute an alternative approach for cancer immunotherapy. POx-Mannose (Man) nanovaccines generate antigen-specific T-cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)-Man nanovaccines. This anti-tumor effect induced by the POx-Man nanovaccines is mediated by a CD8+-T cell-dependent mechanism, in contrast to the PEG-Man nanovaccines. POx-Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD-1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti-tumor effect induced by the combination of nanovaccines with the inhibition of both TAM- and PD-1-inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients.

Original languageEnglish
Article number2300299
JournalAdvanced Science
Volume10
Issue number25
DOIs
StatePublished - 5 Sep 2023

Funding

FundersFunder number
FCT-MCTES
FCT‐MCTESUTAP‐EXPL/NPN/0041/2021, UIDB/04138/2020, EXPL/MED‐QUI/1316/2021, PTDC/BTM‐SAL/4350/2021, UIDP/04138/2020
Fundação para a Ciência e Tecnologia-Ministério da Ciência, Tecnologia e Ensino Superior
Fundação para a Ciência e Tecnologia‐Ministério da Ciência, Tecnologia e Ensino Superior
Morris Kahn FoundationSFRH/BD/131969/2017
National Institutes of Health
Israel Cancer Research FundPROF‐18‐682
Israel Cancer Research Fund
Melanoma Research Alliance615808
Melanoma Research Alliance
European Research Council101113390, 835227
European Research Council
Israel Science Foundation1969/18
Israel Science Foundation
la Caixa” FoundationLCF/TR/CD20/52700005, LCF/PR/HR19/52160021, LCF/PR/HR22/52420016

    Keywords

    • anti-PD-1
    • nanovaccines
    • poly(2-oxazoline)s
    • tumor immune microenvironment
    • tumor-associated macrophages

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