Modulation of tumor microenvironment for immunotherapy: focus on nanomaterial-based strategies

Abstract

Recent advances in the field of immunotherapy have profoundly opened up the potential for improved cancer therapy and reduced side effects. However, the tumor microenvironment (TME) is highly immunosuppressive, therefore, clinical outcomes of currently available cancer immunotherapy are still poor. Recently, nanomaterial-based strategies have been developed to modulate the TME for robust immunotherapeutic responses. In this review, the immunoregulatory cell types (cells relating to the regulation of immune responses) inside the TME in terms of stimulatory and suppressive roles are described, and the technologies used to identify and quantify these cells are provided. In addition, recent examples of nanomaterial-based cancer immunotherapy are discussed, with particular emphasis on those designed to overcome barriers caused by the complexity and diversity of TME.

Keywords: characterization and quantification of immunoregulatory cells; combination therapy; drug delivery; nanoparticles; tumor immunology.

Figure 1

The cancer-immunity cycle in tandem with a summary of stimulatory and inhibitory components. As depicted by Chen and Mellman, this cycle is comprised of 1) release of tumor cell antigens by dying cancer cells, 2) antigen presentation by DCs, 3) priming and activation of T cells, 4) trafficking and 5) infiltration of activated T cells to tumors, 6) recognition of tumor cells by activated T cells, and 7) killing of tumor cells. The stimulatory and inhibitory factors together form an immune regulatory network for the modulation of cancer-immunity cycle. This figure has been modified from and .

Figure 2

Development of nanovaccines for promoting immunostimulatory effects to “fuel the engine” A) LCP-based delivery of mRNA vaccine for an enhanced immune response against melanoma. Adapted with permission from , copyright 2017 Elsevier. B) Albumin-mediated enhanced CAR-T cell activity for solid tumors. Adapted with permission from , copyright 2019 American Association for the Advancement of Science C) Cancer cell membrane-coated adjuvant NPs with mannose modification for anticancer vaccination. Adapted with permission from , copyright 2018 American Chemical Society. D) Erythrocyte membrane-coated NPs as vaccine for antitumor immunity against melanoma. Adapted with permission from , copyright 2015 American Chemical Society.

Figure 3

Development of nanoimmunotherapeutics for overcoming immunosuppressive barriers to “releasing the brake”. A) Local blockade of IL-10 and CXCL 12 using LPD for antitumor response for pancreatic cancer. Adapted with permission from , copyright 2018 American Chemical Society. B) Inhibiting PI3 kinase-γ using AEAA-targeted PLGA in both myeloid and plasma cells to remodel the suppressive TME in pancreatic cancer. Adapted with permission from , copyright 2019 Elsevier. C) Liposome-mediated delivery of vasodilator hydralazine for nanoparticle penetration in advanced desmoplastic melanoma. Adapted with permission from , copyright 2019 American Chemical Society. D) Immunotherapeutic strategy for melanoma via dual-targeting NPs delivering siRNA to TAMs. Adapted with permission from , copyright 2017 American Chemical Society.

Figure 4

Development of nanoimmunotherapeutics for combination therapy. A) NP-mediated co-delivery of mitoxantrone (MIT) and celastrol (CEL) to induce chemo-immunotherapy for cancer inhibition and tumor dormancy in desmoplastic melanoma. Adapted with permission from , copyright 2018 American Chemical Society. B) NP-based co-delivery of Quercetin (Q) and Alantolactone (A) for antitumor responses through synergistic ICD. Adapted with permission from , copyright 2019 American Chemical Society. C) Synergistic and low adverse effect cancer immunotherapy by LPD-mediated immunogenic chemotherapy and locally expressed PD-L1 trap in combination with oxaliplatin for colorectal cancer. Adapted with permission from , copyright 2018 Nature Publishing Group. D) LCP-mediated relaxin gene delivery for synergistic effect with checkpoint inhibition in liver metastasis. Adapted with permission from , copyright 2019 Nature Publishing Group.