Tumor-treating fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy

Cancer Immunol Immunother. 2020 Jul;69(7):1191-1204. doi: 10.1007/s00262-020-02534-7. Epub 2020 Mar 6.


Tumor-treating fields (TTFields) are alternating electric fields in a specific frequency range (100-300 kHz) delivered to the human body through transducer arrays. In this study, we evaluated whether TTFields-mediated cell death can elicit antitumoral immunity and hence would be effectively combined with anti-PD-1 therapy. We demonstrate that in TTFields-treated cancer cells, damage-associated molecular patterns including high-mobility group B1 and adenosine triphosphate are released and calreticulin is exposed on the cell surface. Moreover, we show that TTFields treatment promotes the engulfment of cancer cells by dendritic cells (DCs) and DCs maturation in vitro, as well as recruitment of immune cells in vivo. Additionally, our study demonstrates that the combination of TTFields with anti-PD-1 therapy results in a significant decline of tumor volume and increase in the percentage of tumor-infiltrating leukocytes in two tumor models. In orthotopic lung tumors, these infiltrating leukocytes, specifically macrophages and DCs, showed elevated expression of PD-L1. Compatibly, cytotoxic T-cells isolated from these tumors demonstrated increased production of IFN-γ. In colon cancer tumors, T-cells infiltration was significantly increased following long treatment duration with TTFields plus anti-PD-1. Collectively, our results suggest that TTFields therapy can induce anticancer immune response. Furthermore, we demonstrate robust efficacy of concomitant application of TTFields and anti-PD-1 therapy. These data suggest that integrating TTFields with anti-PD-1 therapy may further enhance antitumor immunity, hence achieve better tumor control.

Keywords: Anti-PD-1; Autophagy; ER stress; Immunogenic cell death; Tumor-treating fields.

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology*
  • Apoptosis
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / therapy*
  • Carcinoma, Lewis Lung / immunology
  • Carcinoma, Lewis Lung / pathology
  • Carcinoma, Lewis Lung / therapy*
  • Cell Proliferation
  • Combined Modality Therapy
  • Electric Stimulation Therapy / methods*
  • Female
  • Humans
  • Immunogenic Cell Death*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Liver Neoplasms / therapy
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Immunological
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor