Journal Article

Sorafenib plus memory-like natural killer cell immunochemotherapy boosts treatment response in liver cancer

Yaghmai, Vahid, Eresen, Aydin, Zhang, Zigeng, Chen, Zhilin, Yu, Zeyang, Hou, Qiaoming, Yu, Guangbo, Zhang, Zhuoli

2024

Overview

Background Heterogeneity of hepatocellular carcinoma (HCC) presents significant challenges for therapeutic strategies and necessitates combinatorial treatment approaches to counteract suppressive behavior of tumor microenvironment and achieve improved outcomes. Here, we employed cytokines to induce memory-like behavior in natural killer (NK) cells, thereby enhancing their cytotoxicity against HCC. Additionally, we evaluated the potential benefits of combining sorafenib with this newly developed memory-like NK cell ( p NK) immunochemotherapy in a preclinical model. Methods HCC tumors were grown in SD rats using subcapsular implantation. Interleukin 12/18 cytokines were supplemented to NK cells to enhance cytotoxicity through memory activation. Tumors were diagnosed using MRI, and animals were randomly assigned to control, p NK immunotherapy, sorafenib chemotherapy, or combination therapy groups. NK cells were delivered locally via the gastrointestinal tract, while sorafenib was administered systemically. Therapeutic responses were monitored with weekly multi-parametric MRI scans over three weeks. Afterward, tumor tissues were harvested for histopathological analysis. Structural and functional changes in tumors were evaluated by analyzing MRI and histopathology data using ANOVA and pairwise T-test analyses. Results The tumors were allowed to grow for six days post-cell implantation before treatment commenced. At baseline, tumor diameter averaged 5.27 mm without significant difference between groups ( p  = 0.16). Both sorafenib and combination therapy imposed greater burden on tumor dimensions compared to immunotherapy alone in the first week. By the second week of treatment, combination therapy had markedly expanded its therapeutic efficacy, resulting in the most significant tumor regression observed (6.05 ± 1.99 vs. 13.99 ± 8.01 mm). Histological analysis demonstrated significantly improved cell destruction in the tumor microenvironment associated with combination treatment (63.79%). Interestingly, we observed fewer viable tumor regions in the sorafenib group (38.9%) compared to the immunotherapy group (45.6%). Notably, there was a significantly higher presence of NK cells in the tumor microenvironment with combination therapy (34.79%) compared to other groups (ranging from 2.21 to 26.50%). Although the tumor sizes in the monotherapy groups were similar, histological analysis revealed a stronger response in p NK cell immunotherapy group compared to the sorafenib group. Conclusions Experimental results indicated that combination therapy significantly enhanced treatment response, resulting in substantial tumor growth reduction in alignment with histological analysis.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Animals / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - therapeutic use / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - immunology / Carcinoma, Hepatocellular - pathology / Carcinoma, Hepatocellular - therapy / Care and treatment / Cell activation / Cell Line, Tumor / Chemotherapy / Clinical outcomes / Combination therapy / Combined Modality Therapy / Cytokines / Cytotoxicity / Development and progression / Diagnosis / Disease Models, Animal / Evaluation / FDA approval / Functional magnetic resonance imaging / Gastrointestinal system / Gastrointestinal tract / Health aspects / Health Promotion and Disease Prevention / Hepatocellular carcinoma / Hepatocytes / Humans / Immune system / Immunologic Memory - drug effects / Immunotherapy / Immunotherapy - methods / Inhibitor drugs / Interleukin 12 / Interleukins / Killer cells / Killer Cells, Natural - immunology / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - immunology / Liver Neoplasms - pathology / Liver Neoplasms - therapy / Magnetic resonance imaging / Male / Medicine/Public Health / Memory-like natural killer cell immunotherapy / Natural killer cells / Niacinamide - analogs & derivatives / Niacinamide - pharmacology / Niacinamide - therapeutic use / Oncology / Patient outcomes / Patients / Phenylurea Compounds - administration & dosage / Phenylurea Compounds - pharmacology / Phenylurea Compounds - therapeutic use / Rats / Sorafenib / Sorafenib - pharmacology / Sorafenib - therapeutic use / Structure-function relationships / Surgical Oncology / Surgical techniques / Targeted cancer therapy / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors