Dendritic Cells In Tumor-draining Lymph Nodes Research Articles

Albumin-Hitchhiking Drug Delivery to Tumor-Draining Lymph Nodes Precisely Boosts Tumor-Specific Immunity through Autophagy Modulation of Immune Cells.

Tumor-draining lymph nodes (TDLNs) are the first sites where tumor components reach and dendritic cells (DCs) present tumor-associated antigens to T cells. DCs rely on autophagy to process tumor antigens into epitope peptides to form epitope-MHC complexes. Selective delivery of autophagy-stimulating drugs to TDLNs may be a precise strategy to boost chemotherapy-induced antitumor immunity. Here, a multistage stimulating strategy is proposed to activate the antitumor immunity cascade by inducing immunogenic death of tumor cells and elevating antigen presentation of DCs in TDLNs. A tumor-microenvironment-responsive "albumin-hitchhiking" micelle is established by self-assembling tumor-targeting oxaliplatin prodrug and lipophilized trehalose prodrug. This demonstrates that lipophilic modification of trehalose with a DSPE tail and the precise exposure in the tumor site enhances its binding to endogenous albumin and realizes TDLNs-selective reflux, where it upregulates antigen processing and presentation of DCs. This study introduces an approach for targeted delivery to TDLNs and provides insights into mechanisms of autophagy in tumor-specific immunity.

Recruitment of dendritic cells using ‘find-me’ signaling microparticles for personalized cancer immunotherapy

Therapeutic cancer vaccines have attracted attention because of their potential to prime cytotoxic T cells, which are highly antigen (Ag)-specific, allowing personalized cancer immunotherapy. However, because of their low immunogenicity, cancer vaccines have been used in only a few types of cancers in clinics, primarily because of the poor Ag presentation of dendritic cells (DCs). To address these limitations of cancer vaccines, we show that ‘find-me’ signaling polymeric microparticles (F-PMs) bearing tumor lysate as an Ag can efficiently recruit DCs and facilitate antigen presentation. When subcutaneously injected into tumor-bearing mice, F-PMs significantly increased mature DCs in tumor-draining lymph nodes by eliciting adenosine triphosphate (ATP)-induced chemotaxis, resulting in high antitumor efficacy. CD8+ cytotoxic T cells were remarkably enriched in the tumor microenvironment following co-administration of an immune checkpoint inhibitor with F-PMs. We demonstrated that F-PMs elicit a robust antitumor immune response, which may provide a promising therapeutic option for cancer treatment.

Antigen-Capturing Mesoporous Silica Nanoparticles Enhance the Radiation-Induced Abscopal Effect in Murine Hepatocellular Carcinoma Hepa1-6 Models.

Immunomodulation by radiotherapy (RT) is an emerging strategy for improving cancer immunotherapy. Nanomaterials have been employed as innovative tools for cancer therapy. This study aimed to investigate whether mesoporous silica nanoparticles (MSNs) enhance RT-mediated local tumor control and the abscopal effect by stimulating anti-cancer immunity. Hepa1-6 murine hepatocellular carcinoma syngeneic models and immunophenotyping with flow cytometry were used to evaluate the immune responses. When mice harboring bilateral tumors received 8 Gy of X-rays on a single tumor, the direct injection of MSNs into irradiated tumors enhanced the growth inhibition of irradiated and unirradiated contralateral tumors. MSNs enhanced RT-induced tumor infiltration of cytotoxic T cells on both sides and suppressed RT-enhanced infiltration of regulatory T cells. The administration of MSNs pre-incubated with irradiated cell-conditioned medium enhanced the anti-tumor effect of anti-PD1 compared to the as-synthesized MSNs. Intracellular uptake of MSNs activated JAWS II dendritic cells (DCs), which were consistently observed in DCs in tumor-draining lymph nodes (TDLNs). Our findings suggest that MSNs may capture tumor antigens released after RT, which is followed by DC maturation in TDLNs and infiltration of cytotoxic T cells in tumors, thereby leading to systemic tumor regression. Our results suggest that MSNs can be applied as an adjuvant for in situ cancer vaccines with RT.

A Novel Immunomodulator Delivery Platform Based on Bacterial Biomimetic Vesicles for Enhanced Antitumor Immunity.

T cell activation-induced cell death (AICD) during tumor pathogenesis is a tumor immune escape process dependent on dendritic cells (DCs). Proper immune-modulatory therapies effectively inhibit tumor-specific CD8+ T cell exhaustion and enhance antitumor immune responses. Here, high-pressure homogenization is utilized to drive immunomodulator IL10-modified bacteria to extrude through the gap and self-assemble into bacterial biomimetic vesicles exposing IL10 (IL10-BBVs) on the surface with high efficiency. IL10-BBVs efficiently target DCs in tumor-draining lymph nodes and thus increase the interaction between IL10 on BBVs and IL10R on DCs to suppress AICD and mitigate CD8+ T cell exhaustion specific to tumor antigens. Two subcutaneous peripheral injections of IL10-BBVs 1 week apart in tumor-bearing mice effectively increase systemic and intratumoral proportions of CD8+ T cells to suppress tumor growth and metastasis. Tumor-specific antigen E7 is enclosed into the periplasm of IL10-BBVs (IL10-E7-BBVs) to realize concurrent actions of the immunomodulator IL10 and the tumor antigen human papillomavirus (HPV) 16E7 in lymph nodes, further enhancing the antitumor effects mediated by CD8+ T cells. The development of this modified BBV delivery platform will expand the application of bacterial membranes and provide novel immunotherapeutic strategies for tumor treatment.

Radiation-induced abscopal effect and its enhancement by programmed cell death 1 blockade in the hepatocellular carcinoma: A murine model study.

Background/AimsThe abscopal effect, a rare phenomenon induced by radiation, can be reinforced by immunotherapy. Although radiation therapy and immunotherapy are increasingly being utilized for the treatment of hepatocellular carcinoma (HCC), whether immunotherapy could boost the abscopal effect remains unclear. In this study, we aimed to elucidate the immunological mechanisms underlying the abscopal effect induced by the combination of irradiation and immunotherapy in a murine HCC model.MethodsA syngeneic HCC mouse model was established by transplanting murine Hepa 1–6 HCC cells into both hind legs of immunocompetent C57BL/6 mice. The tumors on the right hind legs were irradiated, and abscopal effects were observed in the non-irradiated tumors on the left hind leg with or without the coadministration of anti-programmed cell death 1 (PD-1) antibodies. Flow cytometric analyses were performed to analyze the distributions of immune cells infiltrating both irradiated and non-irradiated tumors and the tumor-draining lymph nodes (TDLNs).ResultsAdministration of 16 Gy in two fractions more effectively inhibited the growth of both irradiated and non-irradiated tumors with higher tumor infiltration of cytotoxic T cells than 8 Gy did in a single fraction. The higher dose also increased activated dendritic cells in TDLNs, which had higher expression of the programmed cell death ligand 1. Coadministration of anti-PD-1 antibodies significantly enhanced the abscopal effect and increased infiltration of activated cytotoxic T cells in both irradiated and non-irradiated tumors.ConclusionsOur findings show that adding anti-PD-1 therapy to radiation enhanced the abscopal effect in a syngeneic murine model of HCC.

In Situ Dendritic Cell Vaccine for Effective Cancer Immunotherapy

A cancer vaccine is an important form of immunotherapy. Given their effectiveness for antigen processing and presentation, dendritic cells (DCs) have been exploited in the development of a therapeutic vaccine. Herein, a versatile polymersomal nanoformulation that enables generation of tumor-associated antigens (TAAs) and simultaneously serves as adjuvant for an in situ DC vaccine is reported. The chimeric cross-linked polymersome (CCPS) is acquired from self-assembly of a triblock copolymer, polyethylene glycol-poly(methyl methyacrylate- co-2-amino ethyl methacrylate (thiol/amine))-poly 2-(dimethylamino)ethyl methacrylate (PEG-P(MMA- co-AEMA (SH/NH2)-PDMA). CCPS can encapsulate low-dose doxorubicin hydrochloride (DOX) to induce immunogenic cell death (ICD) and 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), a photosensitizer to facilitate photodynamic therapy (PDT) for reactive oxygen species (ROS) generation. This combination is able to enhance the population of TAAs and DC recruitment, eliciting an immune response cascade. In addition, CCPS with primary and tertiary amines act as adjuvant, both of which can stimulate DCs recruited to form an in situ DC vaccine after combination with TAAs for MC38 colorectal cancer treatment. In vivo results indicate that the all-in-one polymersomal nanoformulation (CCPS/HPPH/DOX) increases mature DCs in tumor-draining lymph nodes (tdLNs) and CD8+ T cells in tumor tissues to inhibit primary and distant MC38 tumor growth following a single intravenous injection with a low dose of DOX and HPPH.

TLR7 Ligand Potentiates GM-CSF-Initiated Antitumor Immunity Through Activation Of Plasmacytoid Dendritic Cells

Vaccination with irradiated granulocyte macrophage-colony stimulating factor (GM-CSF)-transduced autologous tumor cells (GVAX) has been shown to induce therapeutic antitumor immunity presumably through the activated maturation of myeloid dendritic cells (DCs). However, its effectiveness is limited, and little is known about the biological properties related to GM-CSF-sensitized DCs (GM-DCs) in tumor-draining lymph nodes (TDLNs). We therefore attempted to enhance the antitumor effect of GVAX therapy by identifying the key pathways in GM-DCs in TDLNs. We initially confirmed that syngeneic mice subcutaneously (s.c.) injected with poorly immunogenic Lewis lung carcinoma (LLC) cells transduced with Sendai virus encoding GM-CSF (LLC/SeV/GM) significantly rejected the tumor growth. Using cDNA microarrays, we obtained a large number of gene expression data from CD86+ GM-DCs and control DCs in TDLNs, and found that the expressions of type I interferons (IFNs)-related genes, including IRF7 and TLR7, known to be abundantly expressed in plasmacytoid DCs (pDCs), were upregulated in GM-DCs. Indeed, to further activate pDCs, mice s.c. challenged with LLC/SeV/GM cells in combination with a TLR7 ligand, imiquimod, but not a TLR4 ligand, LPS, significantly suppressed the tumor growth compared with mice treated with LLC/SeV/GM cells alone. In contrast, pDCs-depleted mice challenged with LLC/SeV/GM cells facilitated the tumor growth, strongly suggesting that pDCs are essential immune subpopulation in exerting GM-CSF-initiated antitumor effects. Furthermore, the additional use of imiquimod overcame the refractoriness of therapeutic vaccines with irradiated LLC/SeV/GM cells in mice with pre-established LLC tumors. Moreover, similar improvement of GVAX therapy was also observed in a mouse model of CT26 colorectal cancer. Mechanistically, mice treated with the combined vaccination displayed increased cell ratio of PDCA-1+ pDCs and expression levels of CD86, CD9, which correlate with an antitumor phonetype, and Siglec-H, which promote CD8+ T cell proliferation, in TDLNs. Indeed, allogeneic MLR test showed that bone marrow-derived pDCs matured by in vitro culture with GM-CSF plus imiquimod elicited a superior capacity of CD8+ T cell proliferation compared with those with GM-CSF only. On the other hand, the ratio of CD4+CD25+FoxP3+ regulatory T cells (Tregs) was decreased in TDLNs mice treated with the combined vaccination. These findings collectively elucidated that pDCs play positive roles in GM-CSF-initiated antitumor immunity and that further activation of pDC by imiquimod targeting TLR7-IRF7 dependent type I IFNs pathway enhance the antitumor effects of GM-CSF-based tumor vaccination. Disclosures: No relevant conflicts of interest to declare.

Foxp3+ T Cells Induce Perforin-Dependent Dendritic Cell Death in Tumor-Draining Lymph Nodes

Regulatory T (Treg) cells limit the onset of effective antitumor immunity, through yet-ill-defined mechanisms. We showed the rejection of established ovalbumin (OVA)-expressing MCA101 tumors required both the adoptive transfer of OVA-specific CD8(+) T cell receptor transgenic T cells (OTI) and the neutralization of Foxp3(+) T cells. In tumor-draining lymph nodes, Foxp3(+) T cell neutralization induced a marked arrest in the migration of OTI T cells, increased numbers of dendritic cells (DCs), and enhanced OTI T cell priming. Using an in vitro cytotoxic assay and two-photon live microscopy after adoptive transfer of DCs, we demonstrated that Foxp3(+) T cells induced the death of DCs in tumor-draining lymph nodes, but not in the absence of tumor. DC death correlated with Foxp3(+) T cell-DC contacts, and it was tumor-antigen and perforin dependent. We conclude that Foxp3(+) T cell-dependent DC death in tumor-draining lymph nodes limits the onset of CD8(+) T cell responses.