1. Academic Validation
  2. "Cytokine-microfactories" recruit DCs and deliver tumor antigens via gap junctions for immunotherapy

"Cytokine-microfactories" recruit DCs and deliver tumor antigens via gap junctions for immunotherapy

  • J Control Release. 2021 Sep 10;337:417-430. doi: 10.1016/j.jconrel.2021.07.040.
Ling Guo 1 Run-Xiu Wei 1 Ran Sun 1 Qiang Yang 1 Gao-Jie Li 1 Ling-Yun Wang 2 Hai-Bin Luo 3 Min Feng 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-Sen University, University Town, Guangzhou 510006, PR China.
  • 2 Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China. Electronic address: wanglyun@mail.sysu.edu.cn.
  • 3 School of Pharmaceutical Sciences, Sun Yat-Sen University, University Town, Guangzhou 510006, PR China. Electronic address: luohb77@mail.sysu.edu.cn.
  • 4 School of Pharmaceutical Sciences, Sun Yat-Sen University, University Town, Guangzhou 510006, PR China. Electronic address: fengmin@mail.sysu.edu.cn.
Abstract

The majority (~80%) of patients with Cancer do not derive clinical benefit from current immunotherapy, largely due to attenuation of immune responses imposed by robust immunosuppression at tumor sites. Here, a cell-based tumor antigen delivery strategy was developed to boost tumor-specific immunity. Notably, the platform constructing ferric oxide nanoparticle-trained macrophages loading tumor antigens (MFe-N) acquired an immunostimulatory program and functioned as the tumoritropic "cytokine-microfactories" to sustainably produce high levels of multiple therapeutic cytokines (GM-CSF, TNFα, and MIP-1α), which are important in activation of immune cells with antitumor potential. Indeed, MFe-N markedly enhanced recruitment of the professional antigen-presenting cells, dendritic cells (DCs), to the tumor sites of an established B16F10 mouse melanoma model. Subsequently, MFe-N effectively delivered tumor antigens to DCs by gap junction-mediated cell-to-cell transmission. And this trafficking was critical for DC maturation to augment antitumor T-cell responses. Simultaneously, the "cytokine-microfactories" elicited high production of the tumoricidal effectors, and in turn blunted the pro-angiogenic activity of tumor-associated macrophages, resulting in conversion of the tumor-supporting milieu to a tumoricidal function that favored infiltration of antitumor T-cells. The findings provided a novel "cytokine-microfactories" harnessing effective delivery of tumor antigens and production of therapeutic cytokines to robustly promote antigen presentation and reshape the tumor immune milieu for priming antitumor immunity. This can enhance existing T-cell mediated immunotherapeutic potency and extend the curative potential immunotherapy to a broader range of patients.

Keywords

Cell-based tumor antigen delivery; Dendritic cells; GM-CSF; Gap junction channels; MIP-1α; Therapeutic cytokines; Tumor milieu.

Figures