Symphony of nanomaterials and immunotherapy based on the cancer-immunity cycle

Abstract

The immune system is involved in the initiation and progression of cancer. Research on cancer and immunity has contributed to the development of several clinically successful immunotherapies. These immunotherapies often act on a single step of the cancer-immunity cycle. In recent years, the discovery of new nanomaterials has dramatically expanded the functions and potential applications of nanomaterials. In addition to acting as drug-delivery platforms, some nanomaterials can induce the immunogenic cell death (ICD) of cancer cells or regulate the profile and strength of the immune response as immunomodulators. Based on their versatility, nanomaterials may serve as an integrated platform for multiple drugs or therapeutic strategies, simultaneously targeting several steps of the cancer-immunity cycle to enhance the outcome of anticancer immune response. To illustrate the critical roles of nanomaterials in cancer immunotherapies based on cancer-immunity cycle, this review will comprehensively describe the crosstalk between the immune system and cancer, and the current applications of nanomaterials, including drug carriers, ICD inducers, and immunomodulators. Moreover, this review will provide a detailed discussion of the knowledge regarding developing combinational cancer immunotherapies based on the cancer-immunity cycle, hoping to maximize the efficacy of these treatments assisted by nanomaterials.

Keywords: Cancer immunotherapy; Cancer‒immunity cycle; Drug delivery; ICD inducers; Immunomodulators; Nanomaterials; Photodynamic therapy; Photothermal therapy; Radio sensitizer.

Graphical abstract

Figure 1

Adaptive immunity in cancer therapy. Humoral immunity: APCs take up and present antigens by MHC II molecules to activate CD 4⁺ T cells; CD4⁺ T cells present antigens to B cells, resulting in the secretion of antigen-specific antibodies; antibodies associate with antigens and co-precipitate for digestion by macrophages or induce ADCC effect mediated by NK cells. Cellular immunity: cancer cells are engulfed by APCs; APCs cross-present antigens to naïve CD8⁺ T cells by MHC I molecules, which is accompanied by CTLA-4 expression on primed CD8⁺ T cells; primed CD8⁺ T cells recognize cancer cells via an MHC I/antigen complex and kill cells via the perforin, granzyme and Fas/FasL pathway; however, the association of CTLA-4 or PD-1 with their ligands can induce the dysfunction of primed CD8⁺ T cells.

Figure 2

Cancer-immunity cycle. (1) Release of tumor antigens from damaged or dying cancer cells; (2) uptake and presentation of tumor antigens by APCs; (3) priming and activation of CD4⁺ and CD8⁺ T cells to trigger anticancer humoral and cellular immunity; (4) trafficking of NK cells, tumor antigen-specific antibodies, and CD8⁺ T cells; (5) infiltration and enrichment of NK cells, tumor antigen-specific antibodies, and CD8⁺ T cells into cancer tissues; (6) recognition and eradication of cancer cells via the cytotoxicity of CD8⁺ T cells and antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by NK cells. The design of Fig. 2 was inspired by Fig. 1 of Ref. 20 with the copyright permission. Copyright © 2013 Elsevier Inc.

Figure 3

Immunosuppression in cancer tissues.

Figure 4

Nanomaterials target different stages of the cancer–immunity cycle individually or simultaneously. Currently used nanomaterials mainly induce the ICD of cancer cells, promoting the antigen uptake and maturation of APCs, enhancing the cross-presentation of APCs, and regulating the immunosuppressive microenvironment of cancer tissues.

Figure 5

Liposomes anchoring IL-2-fused Fc and an agonistic CD137 antibody resulted in anticancer immunity without systemic toxicity. (A) Cryo-TEM image of a IL-2-Fc-liposome (anti-CD137 liposomes were similar). (B) CD8⁺ T cell counts were determined following the treatment of polyclonal T cells from C57Bl/6 mice with soluble or liposomal IL-2-Fc (10 ng/mL of protein). (C) secreted IFN-γ was analyzed and then activated T cells were incubated with soluble anti-CD137 or Lipo-αCD137 (final αCD137 concentration: 10 μg/mL). (D) frozen sections of tumor after injections of Alexa-568-labeled αCD137 and IL-2-Fc and Lipo-αCD137 + Lipo-IL2-Fc. (E) tumor sizes in C57Bl/6 mice following treatment with αCD137 + IL-2-Fc, Lipo-αCD137 + Lipo-IL-2-Fc, or Lipo-IgG. (F) Bioluminescence images of C57BL/6 mice carrying luciferase-expressing B16F10 tumors, after treatment with Lipo-αCD137 + Lipo-IL-2-Fc or Lipo-IgG. Reprinted with the permission from Ref. 115. Copyright © 2019 Nature Publishing Group.

Figure 6

A dual immunotherapy nanoparticle targeting PD-1 and OX40 improved anticancer immunity. (A) Schematic of DINP-facilitated enhancement of combination immunotherapy. (B) images of nanoparticles before and after antibody conjugation (scale bar: 100 nm). (C) tumor size and survival curves of C57BL/6 mice with B16F10 tumors following treatment with different drugs. (D) immunofluorescent images of tumors after treatment of different drugs. Reprinted with the permission from Ref. 123. Copyright © 2018 WILEY-VCH Publishing Group.

Figure 7

Photothermal therapy with immune-adjuvant nanoparticles induced anticancer immunity. (A) Schematic of immune-adjuvant nanoparticle constructed by PLGA loaded with ICG and R837 and its effect on immune system. (B) tumor volume of 4T1 and CT26 distant tumors following the indicated treatment of the primary tumor. (C) CD4⁺ and CD8⁺ T cells counts of distant tumors following the indicated treatment of the primary tumor. Reprinted with the permission from Ref. 145. Copyright © 2016 Nature Publishing Group.

Figure 8

Gold nanoparticles in situ generated in B16F10 and DCs for the combination of PPT and immunotherapy. (A) Schematic of construction and immunological functions of AUNP@DC_B16F10. (B) TEM images of AUNP@DC_B16F10. (C) temperature change (ΔT) of AuNP, AuNP@DC_L929, and AuNP@DC_B16F10. (D) images presenting live/dead cells after treatment with AuNP@DC_B16F10 or/and laser. (E) primary tumor volume following the indicated treatment. (F) distant tumor weight following the indicated treatment. (G) DC maturation following the indicated treatment. (H) CD4⁺ T cell count after the indicated treatment. Reprinted with the permission from Ref. 161. Copyright © 2019 ACS Publishing Group.

Figure 9

ROS generation in photodynamic therapies.

Figure 10

NIR triggered PDT combinatorial therapy with immune checkpoint blockade. (A) Schematic showing the anticancer function of UCNP-Ce6-R837. (B) tumor volume of primary and distant CT26 tumors following the indicated treatment; the level of CD8⁺ CTL cells (C), Treg cells (D) and the CD8⁺ CTL/Treg ratio (E) in distant tumors, and IFN-γ cytokine levels in sera (F) from mice following the indicated treatment. Reprinted with the permission from Ref. 215. Copyright © 2017 ACS Publishing Group.

Figure 11

In situ vaccine elicited by combined RT + BNP. Reprinted with the permission from Ref. 217. Copyright © 2019 John Wiley and Sons Group.

Figure 12

The scheme of OSPS mediated combinatory cancer therapy. Reprinted with the permission from Ref. 218. Copyright © 2019 John Wiley and Sons Group.

Figure 13

Anticancer immune response induced by OSPS. (A) OSPS-mediated tumor inhibition and lung metastasis. (B) Growth curves of primary tumors in 4T1 tumor-bearing mice. (C) Growth curves of distant tumors in 4T1 tumor-bearing mice. (D) H&E staining of lung metastasis in 4T1 tumor-bearing mice. (E) Number of metastatic nodules in 4T1 tumor-bearing mice (F) The Kyn/Trp ratio in primary tumors in 4T1 tumor-bearing mice. (G) Population of CD3⁺CD8⁺ T cells in distant tumors. (H) IFN-γ producing T-cells in distant tumors. (I) Treg cells in distant tumors. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, n = 5. CSPN, nanoparticles without NLG919. Reprinted with the permission from Ref. 218. Copyright © 2019 John Wiley and Sons Group.