Synergistic effect of Abraxane that combines human IL15 fused with an albumin-binding domain on murine models of pancreatic ductal adenocarcinoma

Fei-Ting Hsu; Chang Liang Tsai; I-Tsang Chiang; Keng-Hsueh Lan; Po-Fu Yueh; Wen-Yi Liang; Chi-Shuo Lin; Yee Chao; Keng-Li Lan

doi:10.1111/jcmm.17220

Synergistic effect of Abraxane that combines human IL15 fused with an albumin-binding domain on murine models of pancreatic ductal adenocarcinoma

J Cell Mol Med. 2022 Apr;26(7):1955-1968. doi: 10.1111/jcmm.17220. Epub 2022 Feb 17.

Authors

Fei-Ting Hsu¹, Chang Liang Tsai², I-Tsang Chiang^{3

4

5

6}, Keng-Hsueh Lan^{7

8}, Po-Fu Yueh^{1

9}, Wen-Yi Liang¹⁰, Chi-Shuo Lin¹¹, Yee Chao¹², Keng-Li Lan^{9

12}

Affiliations

¹ Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
² Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³ Medical administrative center, Show Chwan Memorial Hospital, Changhua, Taiwan.
⁴ Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua, Taiwan.
⁵ Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Lukang, Taiwan.
⁶ Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung, Taiwan.
⁷ Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
⁸ Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁹ Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹⁰ Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan.
¹¹ Department of Radiation Oncology, National Yang Ming Chiao Tung University Hospital, Yilan, Taiwan.
¹² Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.

Abstract

Nab-paclitaxel (Abraxane), which is a nanoparticle form of albumin-bound paclitaxel, is one of the standard chemotherapies for pancreatic ductal adenocarcinoma (PDAC). This study determined the effect of Abraxane in combination with a fusion protein, hIL15-ABD, on subcutaneous Panc02 and orthotopic KPC C57BL/6 murine PDAC models. Abraxane combined with hIL15-ABD best suppressed tumour growth and produced a 40%-60% reduction in the tumour size for Panc02 and KPC, compared to the vehicle group. In the combination group, the active form of interferon-γ (IFN-γ)-secreting CD8⁺ T cells and CD11b⁺ CD86⁺ M1 macrophages in tumour infiltrating lymphocytes (TILs) were increased. In the tumour drainage lymph nodes (TDLNs) of the combination group, there was a 18% reduction in CD8⁺ IFN-γ⁺ T cells and a 0.47% reduction in CD4⁺ CD25⁺ FOXP3⁺ regulatory T cells, as opposed to 5.0% and 5.1% reductions, respectively, for the control group. Superior suppression of CD11b⁺ GR-1⁺ myeloid-derived suppressor cells (MDSCs) and the induction of M1 macrophages in the spleen and bone marrow of mice were found in the combination group. Abraxane and hIL15-ABD effectively suppressed NF-κB-mediated immune suppressive markers, including indoleamine 2,3-dioxygenase (IDO), Foxp3 and VEGF. In conclusion, Abraxane combined with hIL15-ABD stimulates the anticancer activity of effector cells, inhibits immunosuppressive cells within the tumour microenvironment (TME) of PDAC, and produces a greater inhibitory effect than individual monotherapies.

Keywords: Nab-paclitaxel (Abraxane); albumin-binding domain; interleukin-15; pancreatic adenocarcinoma; tumour microenvironment.

Publication types

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

MeSH terms

Albumin-Bound Paclitaxel / pharmacology
Albumin-Bound Paclitaxel / therapeutic use
Albumins / therapeutic use
Animals
CD8-Positive T-Lymphocytes / metabolism
Carcinoma, Pancreatic Ductal* / pathology
Disease Models, Animal
Humans
Interleukin-15
Mice
Mice, Inbred C57BL
Pancreatic Neoplasms* / pathology
Tumor Microenvironment

Substances

Albumin-Bound Paclitaxel
Albumins
Interleukin-15

Abstract

Publication types

MeSH terms

Substances

Grants and funding