Nanotechnology in Regenerative Medicine and Drug Delivery Therapy by Unknown

Author:Unknown
Language: eng
Format: epub
ISBN: 9789811553868
Publisher: Springer Singapore

4.3.4.4 Targeting Regulatory T Cells with Nanomaterials

FOXP3+CD25+CD4+ regulatory T (Treg) cells, as the major immunosuppressive cell population in tumor microenvironment, have a broad range of immunosuppressive activities, such as inhibiting tumor-specific T cell activation and expansion, dampening APC function, ect. Targeting Treg cells has been considered as a plausible immunotherapeutic strategy to rescue antitumor immunity [228]. Currently, Treg-targeted therapy can be achieved by Treg depletion using anti-CD25 or chemotherapeutic drugs (cyclophosphamide and fludarabine). Since CTLA-4 and PD-1 are highly expressed on Treg cells, immune checkpoint blockade with anti-CTLA4 and anti-PD1 is also an effective strategy to attenuate Treg cell activity [177]. Nanotechnology offers great opportunities for Treg-targeted immunotherapy [229]. Li et al. encapsulated CTLA-4 siRNA with PEG-PLA and cationic lipid BHEM-Chol to obtain NPsiCTLA-4 nanocomplexes, which effectively decreased CTLA-4 expression in active T cells about 60–70%. The i.v. injection of NPsiCTLA-4 not only reduced CTLA-4 expression over 60% in CD4+ and CD8+ TILs but also significantly decreased Treg cells in tumors, which consequently enhanced frequency and CTL activity of tumor-infiltrating T cells, leading to robust tumor regression [230]. Imatinib (IMT) is a tyrosine kinase inhibitor that has been reported to decrease Treg cell viability and activity through blocking STAT3 and STAT5 signaling. Ou et al. developed IMT-loaded lipid-PLGA hybrid nanoparticles functionalized with a tLyp1 peptide (IMT/tLyp1-NP) to achieve Treg cell-targeting through Neuropilin-1 (Nrp1) receptor. The results showed that IMT-loaded tLyp1 nanoparticles (IMT/tLyp1-NP) not only suppressed Treg cell differentiation and expansion in vitro but also decreased tumor-infiltrating Treg cells over 30% in mice [231]. The functionalization of PLGA NPs with glucocorticoid-induced TNF receptor family-related protein (GITR) antibody was reported as another effective strategy to enhance the inhibitory effect of IMT on Treg cells [232]. The combination of IMT/tLyp1-NP and anti-CTLA-4 further decreased Treg cells in tumors over 50%, while increasing tumor-infiltrating CD8+ T cells, thereby synergistically inhibiting tumor growth [231]. These studies demonstrate the great potential of nanoparticle-based drug delivery system for modulating Treg cells in tumor microenvironment and improving antitumor immunotherapy.

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