Reprogramming Tumor-Associated Macrophages by Nanoparticle-Based Reactive Oxygen Species Photogeneration

Abstract

Without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment, cancer immunotherapy generally offers limited clinical benefit for established tumors. Tumor-associated macrophages (TAMs) are the critical driver of this immunosuppressive tumor microenvironment, which also promotes tumor metastasis. Here we successfully reprogrammed TAMs to an antitumor M1 phenotype using precision nanoparticle-based reactive oxygen species photogeneration, which demonstrated superior efficiency and efficacy over lipopolysaccharide stimulation. Meanwhile, antigen presentation and T-cell-priming by TAMs were enhanced by inhibiting lysosomal proton pump and proteolytic activity or by promoting tumor associated antigen release in the cytoplasm. The reprogrammed TAMs orchestrate cytotoxic lymphocyte (CTL) recruitment in the tumor and direct memory T-cells toward tumoricidal responses. This strategy could effectively eradicate tumors, inhibit metastasis, and further prevent their recurrence, which holds tremendous promise to realize potent cancer immunotherapy.

Immunomodulatory Nanosystems

“…[162] They synthesized endosome-escaping and TAM-targeting PEG-PLGA NPs for encapsulation of photosensitizers with NH 4 HCO 3 . Shi et al found that the intracellular photogeneration of ROS was able to regulate the reprogramming of TAMs toward M1 phenotype.…”

Materials for Immunotherapy

“…Also in 2017, Goldberg and co‐workers developed PLGA nanoparticles decorated with anti‐PD‐1 to target T cells as well as release R848 (resiquimod, a TLR7/8 agonist) and SD‐208 (a transforming growth factor‐β (TGF‐β) receptor inhibitor) to block the immunosuppressive effects of TGF‐β and potentiate an antitumor response . In 2018, Chen and co‐workers leveraged PLGA nanoparticles to deliver reactive oxygen species (ROS)‐generating species to repolarize tumor‐associated macrophages (TAMs) toward an M1 phenotype and subsequently orchestrate CTL recruitment . Finally, several groups have looked to incorporate photothermal agents into PLGA nanoparticles to enable photothermal therapy (PTT).…”

“…[26] In 2018, Chen and co-workers leveraged PLGA nanoparticles to deliver reactive oxygen species (ROS)-generating species to repolarize tumor-associated macrophages (TAMs) toward an M1 phenotype and subsequently orchestrate CTL recruitment. [27] Finally, several groups have looked to incorporate photothermal agents into PLGA nanoparticles to enable photothermal therapy (PTT). Liu and co-workers showed that PLGA nanoparticles encapsulating indocyanine green (ICG, a PTT agent) and imiquimod (an adjuvant) in combination with free anti-cytotoxic T lymphocyte antigen (CTLA)-4 (a checkpoint inhibitor) led to potent antitumor responses in mice with 4T1 triple negative breast cancer.…”

Engineering Biomaterials to Direct Innate Immunity

“…Most stimuli-responsive NPs rely on hypoxic or acidic dysregulation within tumors. [63] These data emphasize the utility of targeting a biological mechanism of innate immune cells in the primary tumor. [60] There are many approaches that have leveraged pH-regulated degradation in tumors as a means to release a therapeutic, like TNFα.…”

“…To mimic the APC presentation of cytokines to T cells, Eggermont et al recently utilized a polyisocyanopeptide (PIC) backbone appended with controlled densities and ratios of an antibody that binds to a T cell receptor (cluster of differentiation 3, CD3); these constructs also integrated IL-2 or IFNα to stimulate T cell proliferation ( Figure 3B). [63] Copyright 2018, American Chemical Society. Formulations that included either IL-2 or IFNα demonstrated an ability to induce [53] Copyright 2018, The American Association of Immunologists, Inc. B,C) Artificial APCs that control the presentation of cytokines to T cells and D) incorporate T cell costimulatory factors to generate cytotoxic T cells.…”