Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Chia-Jen Wu; Yi-Ting Tsai; I-Jung Lee; Ping-Yi Wu; Long-Sheng Lu; Wen-Shan Tsao; Yi-Jou Huang; Ching-Cheng Chang; Shuk-Man Ka; Mi-Hua Tao

doi:10.1080/2162402X.2018.1477459

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Oncoimmunology. 2018 Jul 23;7(9):e1477459. doi: 10.1080/2162402X.2018.1477459. eCollection 2018.

Authors

Chia-Jen Wu¹, Yi-Ting Tsai^{1

2}, I-Jung Lee^{1

3}, Ping-Yi Wu¹, Long-Sheng Lu^{4

5}, Wen-Shan Tsao¹, Yi-Jou Huang¹, Ching-Cheng Chang⁶, Shuk-Man Ka⁷, Mi-Hua Tao^{1

2

3}

Affiliations

¹ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
² Graduate Institute of Microbiology, National Taiwan University, Taipei, Taiwan.
³ Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
⁴ Department of Radiation Oncology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
⁵ Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.
⁶ National Taiwan University College of Medicine, Graduate Institute of Medical Education & Bioethics, Taipei, Taiwan.
⁷ Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan.

Abstract

Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver per se may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities. Our data showed that radiation and IL-12 combination therapy (RT/IL-12) led to dramatic tumor regression in animals bearing large subcutaneous or orthotopic HCC, induced systemic effect against distant tumor, and significantly prolonged survival. Radiation monotherapy induced tumor regression at early times but afterwards most tumors regained exponential growth, while IL-12 monotherapy only delayed tumor growth. Mechanistic studies revealed that RT/IL-12 increased expression of MHC class II and co-stimulatory molecules CD40 and CD86 on tumor-infiltrating dendritic cells, suggesting an improvement of their antigen presentation activity. RT/IL-12 also significantly reduced accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing production of reactive oxygen species. Accordingly, tumor-infiltrating CD8⁺ T cells and NK cells were significantly activated toward the antitumor phenotype, as revealed by increased expression of CD107a and TNF-α. Together, our data showed that RT/IL-12 treatment could reset the intratumoral immunotolerant state and stimulate activation of antitumor cellular immunity that is capable of eliminating large established HCC tumors.

Keywords: MDSC; Orthotopic HCC; combination therapy; immunomodulation; immunotherapy; radiotherapy; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

This work was supported by Academia Sinica and Ministry of Science and Technology under grants MOST103-2320-B-001-009, MOST 104-0210-01-09-02 and MOST 105-0210-01-13-01.