Intensified NK cell therapy in combination with low-dose chemoradiotherapy against human colorectal cancer

• Published in: Cancer Immunology, Immunotherapy Vol. 72; no. 12; pp. 4089 - 4102
• Main Authors: Nguyen, Huy Phuoc Quang, Bae, Woo Kyun, Park, Myong Suk, Chung, Ik-Joo, Nam, Taek-Keun, Jeong, Jae-Uk, Uong, Tung Nguyen Thanh, Cho, Duck, Kim, Sang-Ki, Yoon, Meesun
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2023; Springer Nature B.V
• Subjects: 5-Fluorouracil; Animals; Antitumor activity; Cancer; Cancer Research; Cell Line, Tumor; Cell therapy; Chemoradiotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - therapy; Cytotoxicity; Degranulation; Humans; Immunology; Immunotherapy; Killer Cells, Natural - metabolism; Major histocompatibility complex; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Natural killer cells; NK Cell Lectin-Like Receptor Subfamily K - metabolism; NKG2 antigen; Oncology; Solid tumors; Tumors; Chemotherapy; Tumor microenvironment; Radiotherapy; NK cell; Colorectal cancer
• ISSN: 0340-7004; 1432-0851; 1432-0851
• DOI: 10.1007/s00262-023-03545-w

The therapeutic potential of adoptive natural Killer (NK) cells immunotherapy in combination with chemoradiotherapy, the main treatment modality for colorectal cancer (CRC), has not yet been explored. Here, we aimed to investigate the efficacy of NK cells to potentiate primary tumor control and improve survival outcomes, especially in combination with low-dose chemoradiotherapy. Ex vivo activated NK cells (> 90% purity) from healthy donors were obtained. NK cells were administered intravenously to the CRC-bearing mice and intensified in vivo in combination with low-dose 5-fluorouracil (0.5 mg/kg or 1 mg/Kg) and irradiated tumors with low doses (2 Gy or 4 Gy). Real-time NK cell cytotoxicity demonstrated a synergistic killing effect of a combination of low-dose chemoradiotherapy, mainly through NKp30 and NKG2D, showing a decrease in NK cell degranulation after blocking NKG2D and NKp30. In vivo tumor characteristics after combination treatment showed decreased CD112, CD155, MICA, and MICB expression. Under the combination strategy, 70% of the mice had free lung metastasis and 90% without secondary gross tumors, indicating suppressed distant metastasis to lung and axillary regions. This combination therapy resulted in significantly synergistic antitumor activity against primary solid tumors compared to chemoradiotherapy only. Furthermore, the intensified NK cell administration showed significantly better primary tumor control and survival outcomes than the non-intensified NK cell administration in a human colorectal HT-29 model treated with low-dose chemoradiotherapy. Optimized NK cell therapy combined with low-dose chemoradiotherapy can provide effective therapeutic potential for intractable cold human colorectal cancer.