TPC-CS nanoparticles as a novel drug delivery system for dendritic cell mediated anti-tumor immunity

  • Rita Ribeiro (Speaker)
  • Neuper, T. (Speaker)
  • Tore-Geir Iversen (Speaker)
  • Markus Steiner (Speaker)
  • Marek Feith (Speaker)
  • Anders Hogset (Speaker)
  • Richard Greil (Speaker)
  • Horejs-Höck, J. (Speaker)

Activity: Talk or presentationPoster presentationscience to science / art to art

Description

Dendritic cells (DCs) are highly specialized cells in orchestrating potent anti-tumor responses through the efficient crosstalk with T cells. According to their phenotypical characterization and functional properties, DCs can be classified in different populations, namely cDC1s and cDC2s, which have the ability to activate CD8+ and CD4+ T cells, respectively. Potent activation of CD8+ T cells by DCs is central to anti-tumor immunity, as CD8+ T cells are crucial in inducing cancer cell death. Moreover, DCs are also essential players in polarizing CD4+T cells, which primarily contribute to anti-tumor immune responses by supporting CD8+ T cells but are also important for long-term anti-tumor immune memory (Paulis, Mandal et al. 2013, Tay, Richardson et al. 2021). Given the essential role of DC-T cell cross talk in effective anti-tumor immune responses, targeting DCs through immunotherapy and vaccination has been a hot topic in the field. Accordingly, novel strategies targeting the immune system have been shifting the paradigm for cancer treatment in recent years and hold great potential as complementary therapies to well-established practices such as surgery, chemotherapy and radiotherapy (Borghaei, Hellmann et al. 2018, Gandhi, Rodríguez-Abreu et al. 2018, Lin, Svensson-Arvelund et al. 2022). Furthermore, there is growing evidence that nanomedicines support an efficient delivery of antigens and adjuvants thus enhancing the immune response against the tumor via DCs, and stimulating patients’ adaptive immunity responses in a specific manner (Riley, June et al. 2019, Yang, Li et al. 2021). Importantly, anti-tumor immunotherapy is only effective if both CD4+ and CD8+ T cells are successfully activated. Hence, the immunosuppressive state of DCs in the tumor microenvironment (TME) must first be successfully overcome to enable efficient DC activation (Humbert and Hugues 2019). As such, the potential success of novel nanovaccines in prompting an effective immune response against the tumor strongly depends on the ability of nanovaccines to robustly activate DCs that are conditioned into a tolerogenic state in the TME. It is widely known that the immunosuppressive TME that occurs in many solid tumors profoundly affects DC activation, thereby impairing the anti-tumor immune responses while enabling tumor growth. Thus, we hypothesize that specific nanoparticles (NPs) have the potential to (re)activate DCs that have been previously tolerogenized by the TME. To assess this, we have developed an in vitro platform to generate human tolerogenic DCs (tolDCs) and used it to demonstrate that chitosan (CS) NPs have the potential to restore DC activation. In the development of our tolDC model and using non-small cell lung cancer as model disease, we have observed that the supernatants (SNs) isolated from related cancer cell line cultures render DCs tolerogenic. More specifically, we observe increased expression of tolerogenic markers such as PD-L1, ILT3, ILT4 and IDO, even upon stimulation with inflammatory mediators. Conversely, secretion of the pro-inflammatory cytokine TNFα is decreased in DCs treated with these SNs. Furthermore, this phenotype is also reflected at the functional level, as we observed an increase in CD4+ Treg cells (CD25+FoxP3+CTLA4+ICOS+PD1+CD127-) in co-cultures systems using tolDCs. Hence, we have developed an in vitro platform that is a valuable tool not only to assess the phenotype of DCs and corresponding T cells in a tumor context but also is a relevant model for proof-of-concept testing of novel therapies as it can be transferred to different tumor models.
Period11 Jun 202316 Jun 2023
Event titleGordon Research Conference – Cancer Nanotechnology: Imaging, Editing and Immunomodulating the Tumor Microenvironment
Event typeConference
LocationWaterville Valley, United States, New HampshireShow on map
Degree of RecognitionInternational

Fields of Science and Technology Classification 2012

  • 106 Biology