Engineering Nanoparticles for Targeted Remodeling of the Tumor Microenvironment to Improve Cancer Immunotherapy

Abstract

Owing to the fast-paced growth and cross-infiltration of oncology, immunology and molecular biology, tumor immunotherapy technology represented by immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapy has lately made remarkable advancements. In comparison with traditional chemotherapy, immunotherapy has the potential to elicit a stronger sustained antitumor immune response in those patients who have advanced malignant malignancies. In spite of the advancements made, a significant number of clinical research works have validated that an extensive proportion of cancer patients still manifest insensitivity to immunotherapy, primarily because of the immunomodulatory interactions between tumor cells and the immunosuppressive tumor microenvironment (TME), together mediating the immune tolerance of tumors and accordingly impacting the positive response to immunotherapy. The intricate immunosuppressive networks formed by stromal cells, inflammatory cells, vasculature, extracellular matrix (ECM), and their secreted cytokines in the TME, play a pivotal role in tumor immune escape. Specific blocking of inhibition pathways in the TME is expected to effectively prevent immune escape and tolerance of tumor cells in addition to their metastasis, accordingly improving the antitumor immune response at various phases of tumor growth. Emerging nanoscale targeted drug carriers truly suit this specific requirement due to their specificity, biocompatibility, and convenience of production. This review emphasizes recent attempts to remodel the tumor immune microenvironment using novel nanoparticles, which include specifically eliminating immunosuppressive cells, reprogramming immune regulatory cells, promoting inflammatory cytokines and blocking immune checkpoints. Targeted remodeling of the immunosuppressive TME using well-designed and fabricated nanoparticles provides a promising strategy for improving the effectiveness of current immunotherapy and is greatly significant.

Keywords: cancer; immunotherapy; nanoparticles; tumor microenvironment; vaccines.

Figure 1

Schematic illustration of tumor cell membrane-coated PLGA nanoparticles that act as nanovaccines to induce antitumor immunity. The PLGA nanoparticles were first loaded with a toll-like receptor 7 agonist of imiquimod (R837) and then coated with a cancer cell membrane whose surface proteins were capable of acting as tumor-specific antigens (NP-R@M). By further surface modification with mannose as a ligand (NP-R@M-M), the obtained nanovaccines showed enhanced cellular uptake capacity by APCs, such as DCs, which are expected to be stimulated to the mature state to trigger an antitumor immune response. Reproduced with permission from , copyright 2018 American Chemical Society.

Figure 2

The mechanism of immune checkpoint blockade using anti-CTLA-4 and anti-PD-1/PD-L1 mAbs. CTLA-4 and PD-1/PD-L1 represent two T cell-inhibitory receptors with independent mechanisms of action. (1) Effective T cell activation requires at least two signals: First, T cells recognize antigen peptide-MHC complex on the APC surface by TCR. Second, co-stimulation through combining CD28 with CD80/CD86. Since CTLA-4 has a greater affinity for CD80/CD86 than CD28, it preferentially binds to the ligand of CD28 and, at sufficient levels, inhibits immune activation. (2) PD-1 is expressed by T cells, while PD-L1 is expressed in tumor cells and tumor-infiltrating immune cells. Inhibition of the interaction between PD-1 and its ligands is expected to significantly enhance the function of T cells and lead to antitumor activity. Accordingly, therapeutic blockade of immunosuppressive checkpoints provides a potential means of boosting antitumor immunity.

Figure 3

Illustration of the mechanisms underlying the combination of PDT with immunogenic ZnP@pyro that enhances the sensitivity of metastatic tumors to PD-L1 blockade immunotherapy. PDT with ZnP@pyro induced ICD and lead to release of TAAs, which were then presented to naïve T cells to stimulate the production and proliferation of tumor-specific effector T cells. In addition, PDT with ZnP@pyro also elicited an inflammatory environment that enhanced infiltration of effector T cells and other immune cells (such as B cells and NK cells) into primary and metastatic tumors. When combined with ICIs targeting PD-L1, PDT with ZnP@pyr not only eradicated the primary tumors, but also rejected the metastatic tumors through a systemic antitumor immune response. Reproduced with permission from , copyright 2016 American Chemical Society.

Figure 4

The main interaction between Th cells and other immune cells in TME. Th2 cells, M2 polarized TAMs, and MDSCs enhance each other's proliferation and phenotypes, in addition to maintaining the immunosuppressive effects of tumors. Together with Tregs, these cells suppress the activity and proliferation of immune effector cells, including Th1, M1 polarized TAMs, and CTLs.

Figure 5

Targeted remodeling of immunosuppressive cells in the TME with nanoparticles to improve cancer immunotherapy. (A) The main strategies for modulating TME on the basis of nanoparticles. (B) Various reported nanoparticles used to improve cancer immunotherapy by remodeling TME.

Figure 6

Illustration of the mechanisms underlying LPD nanoparticles-mediated combination immunotherapy with PD-L1 and CXCL12 trap for the treatment of pancreatic cancer. Plasmids encoding PD-L1 and CXCL12 trap were encapsulated into nanoparticles. Local and transient delivery of the encapsulated plasmids reduced their systemic toxicity and allowed accumulation in perivascular cells. The CXCL12 capture protein secreted from perivascular cells promoted effective capture of CXCL12 chemokines, which not only directly reduced infiltration of immunosuppressive cells (such as MDSCs and Tregs) through the CXCL12 / CXCR4 axis, but also inhibited the expression of PD-L1 by regulating the MAPK pathway. Reproduced with permission from , copyright 2017 American Chemical Society.

Figure 7

Schematic illustration of a microneedle-based transcutaneous drug delivery system loaded with self-assembled immunotherapeutic nanoparticles. (A) The IDO inhibitor 1-MT and hyaluronic acid (HA) were covalently conjugated to form an amphiphilic structure (m-HA), which then self-assembled into nanoparticles to encapsulate the anti-PD-1 antibody (aPD1). Drug release was activated via digestion by hyaluronidase (HAase), which is overexpressed in the TME. The subsequently triggered release of 1-MT blocked the IDO-mediated immunosuppressive pathway in TME, thereby enhancing the ability of aPD1 to block immune checkpoints. (B) The obtained nanoparticles were characterized by an average hydrodynamic size of 151 nm, which was consistent with transmission electron microscopy observation (upper). After 24 h of continuous incubation with HAase, the particles gradually dissociated and the size was decreased to 8 nm (lower). Reproduced with permission from , copyright 2016 American Chemical Society.