ID: 2168

• Title:
  Electrochemotherapy as in situ vaccine
  
  Authors:
  

  Uršic Valentinuzzi, Katja - Institute of Oncology Ljubljana; University of Ljubljana
  Kešar, Urša - Institute of Oncology Ljubljana; University of Ljubljana
  Kamen?ek, Ur?ka - Institute of Oncology Ljubljana; University of Ljubljana
  Kranjc Brezar, Simona - Institute of Oncology Ljubljana; University of Ljubljana
  ?ema?ar, Maja - Institute of Oncology Ljubljana; University of Primorska
  Ser?a, Gregor - Institute of Oncology Ljubljana; University of Ljubljana

  
  
  Abstract:
  Besides direct cytotoxic effects, electrochemotherapy (ECT) can also trigger indirect antitumor
  
  effects via induction of immune system responses. Namely, elevated expression of immunologically
  
  important molecules on tumor cells as well as induction of immunologically recognizable types of cell
  
  death, accompanied with the release of tumor-associated antigens and accumulation of damage-
  
  associated molecular patterns (DAMPs), can induce in situ vaccination effect. Lately, ECT is frequently
  
  combined with immunotherapies. To improve responses and outcomes, the timing of the therapies
  
  in combination is of utmost importance. Therefore, the main goal of this study was to describe and
  
  compare the timeline of the immunologically relevant biomarkers after intratumoral ECT with
  
  bleomycin (BLM), cisplatin (CDDP) and oxaliplatin (OXA). We considered cytotoxic and
  
  immunomodulatory actions of the ECT and investigated if it is sufficient in accomplishing effective in
  
  situ vaccination.
  
  The immunologically important effects of ECT with equieffective doses of BLM, CDDP or OXA were
  
  investigated in three immunologically distinct murine tumor models (B16F10, 4T1 and CT26) in in
  
  vitro and in vivo setting. Specifically, in vitro, the type of cell death and the expression of MHC-I,
  
  MHC-II, PD-L1 and CD-40 were evaluated. In vivo, the antitumor effect of ECT was compared in wild-
  
  type mice and immunocompromised (NUDE) mice and the background immune-related mechanisms
  
  as cell death and infiltration of tumors by different immune cells were compared. For the latter,
  
  cytometric and histological analyses were performed. To assess systemic antitumor effect, the ECT
  
  was also performed on metastatic model established through induced lung metastases.
  
  We showed that the three tumor models are differently sensitive to ECT with the three drugs used;
  
  ECT was more effective in more immunogenic tumors in vivo (CT26 > 4T1 > B16F10). The involvement
  
  of the T cells in the antitumor effect of ECT with CDDP was confirmed by using immunocompromised
  
  mice. Moreover, histological analyses showed that ECT also attracted other immune cells
  
  intatumorally. Furthermore, ECT modified the tumor expression of MHC I, MHC II, PD-L1 and CD40
  
  and induced immunogenic cell death-associated DAMPs; however, the kinetics were cell line- and
  
  drug-specific. Finally yet importantly, ECT with CDDP and BLM also resulted in the abscopal effect.
  
  The study was initiated to systematically evaluate the effects of ECT with CDDP, BLM or OXA in three
  
  tumor models. We showed that the three models are differently sensitive to ECT, i.e., immunogenic
  
  tumors responded better with all the three drugs used. Additionally, we confirmed the involvement
  
  of the immune system in the response. The degree of immune system activation depended on the
  
  type of drug and the type of tumor model. Therefore, the selection of the drug in ECT should be
  
  predominantly based on the tumor immune status. The data obtained in this study will allow us to
  
  design a combinatorial treatment protocol more effectively.
  
  Keywords:
  Electrochemotherapy, mouse models, immune response
  
  Refs:
  
  
  Topic 1:
  12. Biomedical applications
  
  Topic 2:
  6. Cancer treatment and tumor ablation